Review Article Genetic Susceptibility to Chagas Disease...

14
Hindawi Publishing Corporation BioMed Research International Volume 2013, Article ID 284729, 13 pages http://dx.doi.org/10.1155/2013/284729 Review Article Genetic Susceptibility to Chagas Disease: An Overview about the Infection and about the Association between Disease and the Immune Response Genes Christiane Maria Ayo, 1 Márcia Machado de Oliveira Dalalio, 2 Jeane Eliete Laguila Visentainer, 1,2 Pâmela Guimarães Reis, 1 Emília Ângela Sippert, 1 Luciana Ribeiro Jarduli, 1 Hugo Vicentin Alves, 1 and Ana Maria Sell 1,2,3 1 Program of Biosciences Applied to Pharmacy, Department of Clinical Analysis and Biomedicine, Maringa State University, Avenida Colombo 5790, 87020900 Maringa, PR, Brazil 2 Basic Health Sciences Department, Maringa State University, Avenida Colombo 5790, 87020900 Maringa, PR, Brazil 3 Departamento de Ciˆ encias B´ asicas da Sa´ ude, Universidade Estadual de Maring´ a, Avenida Colombo 5790, 87020900 Maringa, PR, Brazil Correspondence should be addressed to Ana Maria Sell; [email protected] Received 29 March 2013; Revised 9 May 2013; Accepted 31 May 2013 Academic Editor: Enrique Medina-Acosta Copyright © 2013 Christiane Maria Ayo et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chagas disease, which is caused by the flagellate parasite Trypanosoma cruzi, affects 8–10 million people in Latin America. e disease is endemic and is characterised by acute and chronic phases that develop in the indeterminate, cardiac, and/or gastro- intestinal forms. e immune response during human T. cruzi infection is not completely understood, despite its role in driving the development of distinct clinical manifestations of chronic infection. Polymorphisms in genes involved in the innate and specific immune response are being widely studied in order to clarify their possible role in the occurrence or severity of disease. Here we review the role of classic and nonclassic MHC, KIR, and cytokine host genetic factors on the infection by T. cruzi and the clinical course of Chagas disease. 1. Introduction 1.1. General Description of Chagas Disease. Chagas disease, or American trypanosomiasis, is an infection caused by the haemoflagellate protozoan Trypanosoma cruzi. It is one of the most important public health problems in Latin America and was first described by Carlos Justiniano Ribeiro das Chagas, a Brazilian physician and scientist [1]. e disease is endemic and is characterised by acute and chronic phases, which develop in the indeterminate, cardiac, and/or gastrointestinal forms. eir course of evolution may be influenced by both genetic and biological variability of the parasite and host [2, 3]. e World Health Organization estimates that approxi- mately 10 million individuals are currently infected with T. cruzi with potential for developing cardiac or gut pathology normally associated with chronic Chagas disease [4] and a large fraction of them will die prematurely, usually from cardiac complications [5]. 1.2. Origin and Discovery of Chagas Disease. e presence of T. cruzi is quite old, totalling about 100 million years. e historic evolution of the trypanosomes began from primitive aquatic invertebrates, and later in the digestive tract of vertebrates such as fish, amphibians, and reptiles. Aſter that, haematophagous insect predators were able to transmit the parasite to different hosts that served as a food source, small to medium wild marsupial mammals, setting the enzootic cycle in the Americas. ereaſter, the cycle expanded to other mammals due to the behaviour of triatomines [6, 7]. e domestic cycle only settled down much later. e spread of disease is due to settlement and concentration of

Transcript of Review Article Genetic Susceptibility to Chagas Disease...

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Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 284729 13 pageshttpdxdoiorg1011552013284729

Review ArticleGenetic Susceptibility to Chagas DiseaseAn Overview about the Infection and about the Associationbetween Disease and the Immune Response Genes

Christiane Maria Ayo1 Maacutercia Machado de Oliveira Dalalio2

Jeane Eliete Laguila Visentainer12 Pacircmela Guimaratildees Reis1 Emiacutelia Acircngela Sippert1

Luciana Ribeiro Jarduli1 Hugo Vicentin Alves1 and Ana Maria Sell123

1 Program of Biosciences Applied to Pharmacy Department of Clinical Analysis and Biomedicine Maringa State UniversityAvenida Colombo 5790 87020900 Maringa PR Brazil

2 Basic Health Sciences Department Maringa State University Avenida Colombo 5790 87020900 Maringa PR Brazil3 Departamento de Ciencias Basicas da Saude Universidade Estadual de Maringa Avenida Colombo 579087020900 Maringa PR Brazil

Correspondence should be addressed to Ana Maria Sell anamsellgmailcom

Received 29 March 2013 Revised 9 May 2013 Accepted 31 May 2013

Academic Editor Enrique Medina-Acosta

Copyright copy 2013 Christiane Maria Ayo et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Chagas disease which is caused by the flagellate parasite Trypanosoma cruzi affects 8ndash10 million people in Latin America Thedisease is endemic and is characterised by acute and chronic phases that develop in the indeterminate cardiac andor gastro-intestinal formsThe immune response during human T cruzi infection is not completely understood despite its role in driving thedevelopment of distinct clinical manifestations of chronic infection Polymorphisms in genes involved in the innate and specificimmune response are being widely studied in order to clarify their possible role in the occurrence or severity of disease Here wereview the role of classic and nonclassic MHC KIR and cytokine host genetic factors on the infection by T cruzi and the clinicalcourse of Chagas disease

1 Introduction

11 General Description of Chagas Disease Chagas diseaseor American trypanosomiasis is an infection caused by thehaemoflagellate protozoan Trypanosoma cruzi It is one of themost important public health problems in Latin America andwas first described by Carlos Justiniano Ribeiro das Chagasa Brazilian physician and scientist [1] The disease is endemicand is characterised by acute and chronic phases whichdevelop in the indeterminate cardiac andor gastrointestinalforms Their course of evolution may be influenced by bothgenetic and biological variability of the parasite and host[2 3]

The World Health Organization estimates that approxi-mately 10 million individuals are currently infected with Tcruzi with potential for developing cardiac or gut pathology

normally associated with chronic Chagas disease [4] anda large fraction of them will die prematurely usually fromcardiac complications [5]

12 Origin and Discovery of Chagas Disease The presence ofT cruzi is quite old totalling about 100 million years Thehistoric evolution of the trypanosomes began from primitiveaquatic invertebrates and later in the digestive tract ofvertebrates such as fish amphibians and reptiles After thathaematophagous insect predators were able to transmit theparasite to different hosts that served as a food source smallto medium wild marsupial mammals setting the enzooticcycle in the AmericasThereafter the cycle expanded to othermammals due to the behaviour of triatomines [6 7]

The domestic cycle only settled down much later Thespread of disease is due to settlement and concentration of

2 BioMed Research International

human populations in pre-Columbian times [8] Howeverthe establishment of Chagas disease itself as a zoonosisoccurred 200ndash300 years ago as a result of deforestationcaused by the expansion of agriculture and livestock whenhumans approached the natural invertebrate niches [9]

There are indications that human infection with T cruzihas occurred since at least nine thousand BC years in popu-lations of the Andean countries it was possible to identifymolecular remnants of T cruzi in mummies of these era andregion [10] and Peruvian ceramics dating from the thirteenthto sixteenth centuries revealed possible representations ofChagas disease including a head with unilateral ocularoedema identical to the Romana signal that often characte-rises the context of acute infection [11]

Charles Darwin observed the behaviour of the triatomineinsect transmitter during his passage through Argentina andwrote in his diary ldquoTheVoyage of the Beaglerdquo that he had beenbitten by the same insect while visiting Chile in 1835The pre-sence of gastric symptoms and his final death caused by heartproblems in 1882 was suggested to be due to Chagas disease[12]

The disease was described for the first time in 1907 whenCarlos Chagas described the trypanosome the transmissioninsect and the syndrome that characterised a new tropicalparasitic disease [1 13]

13 Epidemiology It is estimated that 10 million people areinfectedwithT cruziworldwidemostly in LatinAmerica [4]and about 100 million people are at risk of the disease in theAmericas with a total estimated incidence of 800000 newcases per year [14]

Chagas disease was characterised as a neglected disease ofpoor and rural populations but the progressive urbanisationespecially since the 1940 has made the disease an urbanproblem of medical and social importance The disease hasalso spread from Latin America to nonendemic countrieswith the movements of people from endemic to nonendemiccountries including North America Western Pacific regions(mainly Australia and Japan) and Europe It is estimated thattoday there are over 300000 individuals infectedwithT cruziin the United States over 5500 in Canada over 80000 inEurope and the Western Pacific region more than 3000 inJapan and more than 1500 in Australia [15ndash18] Thus theprevalence incidence and mortality associated with Chagasdisease showed considerable variations in recent decadesmainly due to the impact of control programs migrationof rural and urban populations and socioeconomic changes[14] Although the estimates of prevalence of infection aregradually decreasing the disease still exists

14 Transmission of Chagas Infection The transmission ofChagas infection can be divided into primary and secondarymechanisms the main mechanisms include transmissionthrough insect vectors by blood transfusion contaminatedfood and congenital transmission Secondary mechanismtransmissions may occur by laboratory accidents organtransplants sexual transmissionwounds in contactwith con-taminated sperm or menstrual fluid and hypothetically by

inoculation by criminal or deliberate contamination of foodwith the parasite [9]

The diseasersquos reservoir lies in 100 different mammalspecies of wild animals It is transmitted by several dozens ofinsect species belonging to the family Reduviidae subfamilyTriatominaeThese insects hide in wild animalsrsquo nests or lairsand extract their bloodmeals (wild cycle) In the insect vectorthe trypanosome undergoes several and successive develop-mental stages terminating as a flagellated form that staysin the vectorrsquos rectum At night humans are bitten by theseinsects usually in the facial area (domestic cycle) Ingestion ofthe bloodmeal causes the vector to defecate After awakeningthe victim usually rubs the bite area and pushes the stool withthe trypanosome into the wound or onto the conjunctivaAfter the T cruzi accesses the victimrsquos blood this initiates theacute phase of the disease Widely distributed via the bloodstream the trypanosome sheds its flagellum and penetratestissue cells They proliferate by binary fission within the cells(especially myocardium and meninges) [19]

Transfusion infection is the second most importantepidemiological mechanism in the transmission of Chagasdisease [19] In 1960 theWorld Health Organization (WHO)estimated seven million cases per year due to blood trans-fusions in Latin America and this finding helped changepolicy and practice [14 15] Congenital transmission istransplacental and seems to depend on factors related tothe parasite and the host trypomastigotes penetrate theplacenta through the chorionic epithelium and trophoblasticHofbauer cells (macrophages placenta) where they transforminto amastigotes [20] Oral transmission of Chagas diseasecan occur especially associated with contamination of breastmilk (congenitally) fruit juices and vegetables contaminatedby infected wild vectors [21]

Other forms of exceptional transmission can occur Acci-dents involve researchers and laboratory technicians workingwith the parasite through the blood of infected people andanimals culture media or vector The transmission by coitushas never been proven in humans there are only reportsof trypomastigotes in the blood of menstruation chagasicwomenThe presence of trypomastigotes was found in spermfrom experimentally infected mice and infection was alsodemonstrated after depositing T cruzi in the vagina of rats[19]

15 Clinical Manifestations and Diagnosis Human T cruziinfection evolves from a usually oligosymptomatic acutephase to a chronic disease The biological and genetic vari-ability of the parasite and of the hostmay influence the courseof disease progression [3 22]

The early or acute phase of infection is characterisedby high parasitaemia or trypomastigote circulating forms inthe blood for two to four months [23] During this periodthe mortality ranges from 5 to 10 due to episodes ofmyocarditis and meningocefalite [24 25] The clinical signsassociated with infection are a local inflammatory reactionwith formation of strong swelling in the region of entry of theparasite (chagoma or Romana sign) fever splenomegaly andcardiac arrhythmia [26] The presence of circulating para-sites can be detected by xenodiagnosis haemoculture [27]

BioMed Research International 3

and molecular characterisation of the parasitersquos DNA by thepolymerase chain reaction (PCR) [28] During the acutephase the majority of infected individuals develop a humoraland cellular immune response responsible for the decrease ofparasites in the blood

After that the patients progress to the chronic asymp-tomatic stage that affects most individuals (50 to 60)this condition characterises the indeterminate clinical form(IND) of the disease and it may remain for long periodsof time [23 27] About 20 to 30 develop cardiomyopa-thy that reflects a myocardium progressively damaged byextensive chronic inflammation and fibrosis and in terminalphases usually presents as dilated cardiomyopathy ChronicChagas cardiomyopathy (CCC) is the most relevant clinicalmanifestation causing death from heart failure in endemiccountries and accounts for a significant burden of ischaemicand inflammatory heart diseases in the USA and Europe dueto ldquoglobalisationrdquo of Chagas disease Eight to 10 has thedigestive form characterised by dilation of the oesophagus orcolon (megaoesophagus andmegacolon) Some patients haveassociated cardiac and digestivemanifestations known as themixed or cardiodigestive form [17 29 30]

The transition from acute to chronic phase is accom-panied by a marked decrease in parasitaemia due to themounting of a relatively effective immune response whichkeeps parasite frequency at below detectable levels in thehost To diagnose the disease regardless of stage the sero-logical test is used by detecting antibodies specific to theparasite IgM (acute phase) and IgG (indeterminate andchronic phase) [31] Conventional serological tests includeprimarily immunofluorescence assays (IFA) enzyme-linkedimmunosorbent assays (ELISA) and indirect haemaggluti-nation assays (IHA)These tests were summarised by Afonsoet al [32] Changes in the chronic phase can be revealed byelectrocardiogram clinical diagnosis X-rays and ultrasound[27 33]

16 Host Immune Response There is a consensus that duringT cruzi infection the host immune system induces complexprocesses to ensure the control of parasite growth Theimmune response is crucial for protection against diseasehowever immunological imbalances can lead to heart anddigestive tract lesions in chagasic patients Several studieshave evaluated the innate cellular and humoral immuneresponses in chagasic patients in an attempt to correlateimmunological findings with clinical forms of Chagas dis-ease However in all clinical forms of Chagas disease theinvolvement of cell-mediated immunity is undoubtedly ofmajor importance [34ndash36]

It is also accepted that T cruzi induces a strong activationof the immune system during acute infection and that thedifferent immunological mechanisms triggered during theearly indeterminate stages of the infection may representan essential component of the immune activity observedduring ongoing clinically distinct chronic infection Afterinvasion of infectious metacyclic trypomastigotes in themammalian host T cruzi infects a variety of cell types suchas macrophages and fibroblasts Fibroblasts are numerousin the extracellular matrix of the skin and are refractory

to apoptosis [37] unlike macrophages and cardiomyocytesInfected macrophages initiate the molecular interactions thatmobilise the innate immune response of the host by sec-retion of proinflammatory cytokines like tumour necrosisfactor alpha (TNF-120572) and interleukin- (IL-) 12 [38] Thesecytokines activate Natural Killer (NK) cells to produce inter-feron-gamma (IFN-120574) that acts directly on macrophagesactivating them for antimicrobial activity Activated macro-phages produce nitric oxide (NO) via NO synthase (iNOSNOS2) potent against T cruzi Furthermore the regulatorycytokinesmdashIL-4 IL-10 and transforming growth factor beta(TGF-120573)mdashinhibit the production of NO and trypanocidalactivity of activated macrophages is responsible for disablingthe control of lethal inflammatory effects of type 1 cytokinesproduced during infection [39]

Uncontrolled activation of NK cells andmacrophages canlead to tissue damage According to Vitelli-Avelar et al [40]there is a mixed profile of cytokine production and highlevels of IFN-120574 TNF-120572 and IL-4 favour the generation ofinflammatory mechanisms This intense inflammatory pro-cess during the initial infection is essential to confine the aeti-ologic agent in the intracellular site (limiting infection andsymptoms) and prevent tissue damage but can be determin-ant to immunopathology

The lesions of the acute phase of the disease are charac-terised by the presence of localised inflammatory reactionswith a predominance of mononuclear cells at the foci ofthe pseudocyst ruptures occasionally with the formation ofgranulomas located mainly in muscle and cardiac tissue [17]

There is a robust immune response displayed in the INDdespite the complete lack of clinical disease Many studiesconcerning the cellular immune response in the IND havebeen performed Peripheral blood cells from these patientsproliferate when stimulated with antiepimastigote antibodies[35] Analysis of the expression of activation markers by T-cells showed that INDpatients have a high frequency of CD4+and CD8+ T-cells expressing HLA-DR and CD45RO [33]Moreover the vastmajority of these T-cells do not express thecostimulatory molecule CD28 [35] which suggested that thissubpopulation displayed down-modulatory activity due tointrinsic regulation via CTLA-4 In mice deficiency in eitherclass I- or class II-restricted T-cell populations was observedas a striking similarity in their mortality rate [41] Given thatCD8+ T-cells seem to be the best candidate for tissue destruc-tion it is possible that this regulatorymechanism working intandem with others helps prevent pathology in IND [42]

Despite it being considered for decades that the adaptiveimmune response is the most important protective mecha-nism during chronic infection recent studies have suggestedthe importance of the innate response as a regulatory mech-anism for controlling morbidity during disease Monocytesfrom IND patients in vitro lead to a high expression of IL-10 consistent with a modulatory response CD3-D16+CD56+

and CD3minus CD16+ CD56dim NK cells counts are particularlyhigh suggesting a protective role of this cell subpopulationCD56dim NK cells had more cytotoxic activity and can con-tribute to the control of parasitism Added to this asymp-tomatic patients exhibited Treg cells (CD4+CD25high) NKT

4 BioMed Research International

regulatory cells (CD3minusCD56+CD16+) and macrophage-likeregulatory cells (CD14+CD16+) that encourage the establish-ment and maintenance of the IND form [39 43]

CCC is associated with the presence of an intense inflam-matory infiltrate in the myocardium especially at sites whereT cruzi antigens are observed The infiltrate was composedespecially by CD8+ T-cells IL-7 and IL-15 are critical formaintenance of these cells and their activation state in theheart tissue of CCC [44] CD8+ T-cells are also found in thecirculation Similar to what was described in IND patientsCD8+ and CD4+ cells present high expression of HLA-DRand lower expression of CD28 however here CD4+ cellswere correlated with the expression of TNF-alpha [35 36] aswell as IFN-120574 The latter cytokine is higher in CCC than INDpatients andmay be a key factor in the development of severecardiomyopathy [45] Monocytes from cardiac patients alsoproduce TNF-120572 and IL-10 Although cells from CCC patientsare able to produce IL-10 the ratio of this cytokine seems tobe lower in cardiac patients [45]

During the T cruzi-cardiomyocyte interaction the par-asite has control of the host cell gene expression includingexpression of genes related to immune response inflamma-tion cytoskeletal organisation cell-cell and cell-matrix inter-actions apoptosis cell cycle and oxidative stress [46] Theintense production of cytokines chemokines and nitricoxide that are essential elements of the defensive reaction incardiac tissue can also result in cardiac hypertrophyThe acti-vation of the host cell apoptotic machinery by pathogens isan offensive strategy to eliminate the hostrsquos immune response[47]

Megaoesophagus and megacolon are the major causesof morbidity in the digestive clinical form of chronic Cha-gas disease Inflammatory infiltrates and fibrosis are foundassociated with lesions of muscle cells and of the intramuralnervous system They are composed mainly of CD3+CD4+T lymphocytes CD20+ B lymphocytes CD57+ NK cellsand CD68+ macrophage-like cells [48] Correa-Oliveira etal [45] observed that patients with the gastrointestinal formof Chagas disease demonstrated a significant decrease in theabsolute number of CD3+ T-cells as well as in CD19+ Blymphocytes and an inversion of the CD4CD8 ratio con-trastingwith results fromCCCwhere the ratio of these cells isnormal Chagasic patients with megacolon present increasednumbers of eosinophils and mononuclear cells [49] Thesecells are associatedwith inflammatory processes and can con-tribute to tissue injury through the secretion of cytokinessuch as IL-1 TNF-120572 and IL-6 which activate the cytotoxicprocess [50]

17 Pathogenesis in Chagas Disease Based on the relationshipof parasite and host interaction the mechanisms of patho-genesis in human Chagas disease can be based on two mainhypotheses The first defends the pivotal role of parasitersquospersistence in the host as a major cause of pathology whilethe other postulates that an immune response against self-antigens is responsible for the tissue damage observed inaffected organs of chagasic individuals

T cruzi exhibits multiple strategies to ensure its estab-lishment and persistence in the host Although this parasite

has the ability to infect different organs heart impairmentis the most frequent clinical manifestation of the diseaseCalvet et al [47] reviewed the current understanding ofmole-cules involved in T cruzi-cardiomyocyte recognition themechanism of invasion and the effect of intracellular devel-opment of T cruzi on the structural organisation and molec-ular response of the target cell The nature of the myocardialchanges in the chronic stage has been considered by some tobe an autoimmune phenomenon based on antigenicmimicryin the form of an antibody targeting T cruzi polypeptides[51] More recently however persistence of the parasite in thetissues has been demonstrated [52]

Although the theories are controversial autoreactivityand parasite persistence theories are not mutually exclusiveThe variation in pathologicalmanifestation has been reportedand was related to differences in host immune response suchas the ability to control parasitaemia the strength of inflam-matory reactions and the induction of autoimmune-likeresponses [53]

2 Genetic Factors and Their Influence onChagas Disease

The advance in knowledge about infection and disease haschanged the concept of infectious diseases and the geneticmarkers play an important role in this area [54] The spec-trum of expression of Chagas disease brings strong evidenceof the influence of the genetic factors on its clinical course[55]

The polymorphisms of the genes involved in the innateand specific immune response are being widely studied inorder to clarify their possible role in the occurrence or sever-ity of disease To identify possible host genetic factors thatmay influence the clinical course of Chagas disease the roleof classic and nonclassic major histocompatibility complex(MHC) genes killer cell immunoglobulin-like receptor (KIR)genes and cytokine genes that are involved in the immuneresponse will be addressed

21 Strategy for Screening and Selecting Studies This reviewabout genetic factors and their influence on Chagas diseaseselected original articles carried out on humans that werefound in the databases of PubMed (US National Library ofMedicine) LILACs (Latin American and Caribbean Centeron Information in Health Sciences) and Google ScholarTheresearch period covered included the limit of databases untilMarch 2013 There was no restriction regarding languageIn the PubMed database MeSH (Medical Subject HeadingTerms) were used and in the LILACS descriptors wereused In order to retrieve articles of interest free termswere used in the LILACS and Google Scholar The MeSHterms descriptors and free terms were organized accordingto thematic groups (i) HLA and Chagas disease (ldquoChagasDiseasegeneticsrdquo OR ldquoChagas Diseaseimmunologyrdquo ANDldquoHLAAntigensgeneticsrdquoOR ldquoHLA antigensimmunologyrdquo)(ii) MIC and Chagas disease (ldquoChagas diseasegeneticsrdquoAND ldquoMHC class I-related chain Ardquo) (iii) KIR genes andChagas disease (ldquoChagas diseasegeneticsrdquo AND ldquoReceptorsKIRgeneticsrdquo) (iv) Cytokine genes and Chagas disease

BioMed Research International 5

Potentially relevant citations at electronic databases (n = 173)

Citations which failed in the inclusion no human aimoriginality duplicate articles and double data criteria (n = 139)

Potentially relevant articles for analysis related to immuneresponse genes in association with Chagas disease (n = 34)

Articles which were added from reference list (n = 6)

40 original articles on human infections included in this review

Figure 1 Flow chart of the study for review

(ldquoChagas diseasegeneticsrdquo AND ldquocytokinesgeneticsrdquo ORldquoChemokinesgeneticsrdquo OR ldquoReceptors cytokinegeneticsrdquoThe immune response genes as HLA KIR MIC and cyto-kines and their association with Chagas disease and its clin-ical forms in the American Latin population were presentedThe results were summarized in Figure 1 and the selectedstudies are presented in Tables 1 and 2

22 HLA and Chagas Disease To identify possible host gen-etic factors that may influence the clinical course of Chagasdisease the molecules and genes in the region of the humanleucocyte antigen (HLA) have been analysed in patientspresenting with differing clinical symptoms

The highly polymorphic HLA class I (A B and C) andII (DR DQ and DP) molecules determine the efficiency ofpresentation of the T cruzi epitopes to CD8+ and CD4+ T-cells respectively The type of the presentation could affectthe clinical course of diseases because patients may responddifferently to the same antigen depending on their HLArepertory [56]

HLA alleles and haplotypes associated with Chagas dis-ease are summarized in Table 1

Several HLA alleles and haplotypes have been reportedto be associated with Chagas disease In Venezuela a studycomparing class II allele frequencies between patients andcontrols identified a decreased frequency of DRB1lowast14 andDQB1lowast0303 in patients suggesting independent protectiveeffects to chronic infection in this population In thissame study a higher frequency of DRB1lowast01 DRB1lowast08 andDQB1lowast0501 and a decreased frequency of DRB1lowast1501 werefound in patients with arrhythmia and congestive heartfailure [57] In an endemic area of central Venezuela a higherfrequency of the HLA-DPB1lowast0401 allele and DPB1lowast0401-HLA-DPB1lowast2301 or DPB1lowast0401-DPB1lowast3901 haplotype was

found in patients with cardiac manifestations [58] Sus-ceptibility between HLA-Clowast03 and CCC Venezuelan wasconfirmed [59]

In Chile HLA-B40 antigen in the presence of Cw3 wassignificantly lower in subjects with CCC [60] and was foundin higher expression in patients without evidence of heartdisease in Santiago [61]

An increase of HLA-A31 B39 and DR8 and a decreaseof HLA-DR4 DR5 DQ1 and DQ3 were observed in severalLatin American mestizos from different countries and withCCC [62]

A study in south-eastern Brazil showed that HLA-Alowast30was involved in susceptibility to Chagas disease whereasHLA-DQB1lowast06 was related to protection regardless of theclinical form of the disease [63] and HLA-DR2 was asso-ciated with susceptibility to chronic Chagas disease in asouth Brazilian population [64] However in another studythe polymorphism of HLA-DR and -DQ does not influencethe susceptibility to different clinical forms of Chagas dis-ease or the progression to severe Chagasrsquo cardiomyopathy[65]

The haplotype HLA-DRB1lowast14-DQB1lowast0301 was involvedin resistance to infection with T cruzi in a rural mestizopopulation of southern Peru [66]

In the Mexican population HLA-DR4 and HLA-B39were associated with the infection by the T Cruzi whereasHLA-DR16 was a marker of susceptibility to damage tothe heart and HLA-A68 was related with protection todevelopment of CCC [67]

In Argentina the class II allele HLA-DRB1lowast0409 andDRB1lowast1503 was significantly more prevalent in Chagas dis-ease and DRB1lowast1103 allele was associated with disease resist-ance Increased frequency of DRB1lowast1503 allele was foundamong CCC suggesting susceptibility [68 69]

In Bolivia the frequencies of HLA-DRB1lowast01 and HLA-Blowast1402 were significantly lower in patients suffering frommegacolon as well as in those with ECG alteration andormegacolon compared with a group of IND patientsThe DRB1lowast0102 Blowast1402 and MICAlowast011 alleles were instrong linkage disequilibrium and the HLA-DRB1lowast01-Blowast14-MICAlowast011 haplotype was associated with resistance againstchronic Chagas disease [70]

These different results between the HLA allele and hap-lotypes and Chagas disease could be caused by variability ofHLA allelersquos distribution in different ethnic groups the typingtest (serological or molecular techniques) the methods ofstatistical analyses (simple chi-square test and logistic orlinear regression) and interpretation (119875 value or 119875

119888value that

applies the Bonferroni correction for multiple comparisons)the selection of the patients and the clinical form the num-bers of individuals linkage disequilibrium and biologicalvariability of the parasite Nevertheless genetic factors relatedto the HLA system reflect an important role in susceptibilityor protection to Chagas disease and its clinical forms

23 MIC and Chagas Disease The HLA region containsnot only classical HLA genes but also a wide variety ofimmunologically relevant genes such as nonclassical class Igenes (MICAMICB major histocompatibility complex class

6 BioMed Research International

Table 1 Alleles and haplotypes HLA associated with Chagas disease

HLA class I alleles andhaplotypes

HLA class II alleles andhaplotypes Population Clinical forms Association Reference

aDRB1lowast01 DQB1lowast0303 Venezuela Chronic phase Protection [57]aDRB1lowast1501 CCC Protection [57]aDRB1lowast08 CCC Susceptibility [57]aDRB1lowast01 DQB1lowast0501 CCC Susceptibility [57 58]aDPB1lowast0401aDPB1lowast0401ndashlowast2301aDPB1lowast0401ndashlowast3901 haplotypes CCC Susceptibility [58]

bClowast03 CCC Susceptibility [59]aHLA-B40-Cw3 haplotype Chile CCC Protection [60 61]bHLA-Alowast30 Brazil All clinical form Susceptibility [63]

bDQB1lowast06 All clinical form Protection [63]bDR2 Chronic phase Susceptibility [64]

No association [65]bDRB1lowast14-DQB1lowast0301 haplotype Peru Infection Protection [66]

bHLA-B39 bHLA-DR4 Mexico Infection Susceptibility [67]bHLA-B35 bHLA-DR16 CCC SusceptibilitybHLA-A68 CCC Protection

bDRB1lowast0409 and lowast1503 Argentina Infection Susceptibility [68 69]bDRB1lowast1103 Infection Protection [69]bDRB1lowast1503 CCC Susceptibility [69]

bHLA-Blowast1402 bHLA-DRB1lowast01 Bolivian DG or mixed Protection [70]bHLA-DRB1lowast01-Blowast14-MICAlowast011haplotype Infection Protection [70]

bHLA-B35-MICA-A5haplotype Guatemala CCC Susceptibility [79]

bA31 and B39 bDR8 Latin American mestizos CCC Susceptibility [62]bDR4 DR5 DQ1 DQ3 CCC Protection

a119875 value le 005 or b

119875119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

I chain-related genes A and B) thatmay be involved in diseasepathogenesis

TheMICAmolecules are recognised by lymphocytes T120574120575lymphocytes T120572120573 CD8+ and NK cells via their receptorsNKG2D present on their surfaces in association with theDAP10 molecule an adapter protein membrane [71 72] Thiscomplex NKG2D-MICA activates the phosphorylation oftyrosine residues of themolecule DAP10 triggering a cascadeof cell signalling that ends with the process of cell lysis of thetarget cells [72] A study by Steinle et al [73] showed thatchanging a single amino acidmdasha methionine for a valine atposition 129 of the1205722 domain of the heavy chainmdashcategorisesthe MICA as strong (MICA-129met) and weak (MICA-129val) ligands of NKG2D affecting the activation of NK cells

MICA and MICB are weakly expressed on healthy cellsbut their expression is induced in response to cellular stressin many cell types including epithelial cells fibroblastskeratinocytes endothelial cells and monocytes [74ndash77]

The polymorphism of MICA may be involved in sus-ceptibility to various diseases but it has been suggestedthat this association may be secondary due to the strong

linkage disequilibrium with HLA-B alleles Groh et al [78]found that MICAlowast011 which was closely linked to HLA-Blowast14 and DRB1lowast01 might stimulate T120574120575 cells in the gutmucosa a phenomenon that could relate to megacolonIn Chagas disease the same HLA-DRB1lowast01-Blowast14-MICAlowast011haplotype was associated with resistance against the chronicform [70] MICA-A5 and HLA-B35 synergistically enhancedsusceptibility to CCC [79]

24 Association of KIR Genes and Their HLA Ligands withChagas Disease Other receptors of NK cells that recogniseHLA class I molecules present on the target cells includedKIR (killer cell immunoglobulin-like receptor) [80 81] KIRreceptors are glycoproteins that belong to the immunoglobu-lin superfamily and which are also found in some subpopu-lations of T-cells [82] KIR genes are clustered in the 19q134region and are characterised by both allelic (high numbersof variants) and haplotypic (different numbers of genes forinhibitory and activating receptors on individual chromo-somes) polymorphismsThe specific KIR-HLA combinationsmay regulate NK cell-mediated immunity against infectious

BioMed Research International 7

Table 2 Polymorphisms in cytokines genes and their association with Chagas disease

Geneallelegenotype Population Clinical form Association ReferenceTNFA minus308 minus244 minus236and TNFB Peru Infection and CCC No association [106]

bTNF minus308A Mexico Infection and CCC Susceptibility [108]TNF minus308A Brazil CCC No association [107]aTNF minus238A Brazil Infection Susceptibility [109]aTNF minus1031C and minus308A Colombia CCC Susceptibility [110]aTNFA minus1031TT andminus308GG Colombia CCC Protection [110]aTNFa2 TNFa7 TNFa8TNFb2 TNFb4 TNFd5TNFd7 TNFe2

Brazil CCC DG or mixed Protection [111]

aTNFb7 and TNFd3 Brazil CCC and mixed Susceptibility [111]aTNFa2 Brazil CCC Susceptibility [112]bLTA +80C and LTA +252G Brazil CCC Susceptibility [113]bLTA +80A +252Ahaplotype Brazil CCC Protection [113]

IL6 minus174GC PeruColombia Infection No association [114]bIL minus1RN4CC Mexico CCC Susceptibility [115]bIL1B +5810G allele andIL1B minus31 +395 CT genotype Colombia CCC Susceptibility [116]

aIL10 minus1082A and minus1082AA Brazil CCC Susceptibility [119]IL10 Colombia Infection No association [120]aIFNG +874A and +874AA Colombia Infection Susceptibility [122]aIL4 minus590T Bolivia Infection Protection [124]aIL4RA +148AA CCC Susceptibility [120]aTGFB110C and CC PeruColombia Infection Susceptibility [126]bIL12B 31015840 UTR C and CC Colombia CCC Susceptibility [127]aCXCL9CC and CXCL10GG Brazil CCC Protection [129]CCR5CC CCC Susceptibility [129]abCCR5 minus2554T minus2733G59029G 59029AG59029GG

PeruColombiaVenezuela CCC Susceptibility [130ndash132]

aCCL2 minus2518A and AA Brazil CCC Susceptibility [133]aBAT1 22C 348C Brazil CCC Susceptibility [134]a119875 value le 005 b119875

119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

pathogens and contribute to diverse susceptibility to diseasesand other clinical situations

Several studies have shown the participation ofKIR genesand their ligands in infectious diseases [83ndash89] autoimmuneor inflammatory diseases [90ndash92] cancer [93ndash95] and in thesuccess of transplantation [96] However there are no dataavailable on the role ofKIR genes in the immunopathogenesisof Chagas disease

25 Association of Polymorphisms in Cytokine Genes withChagas Disease Immunomodulatory cytokines secreted byT-cells and macrophages are molecules that act as mediatorsof inflammation and immune response These moleculesare key components in the pathogenesis of many diseasesincluding infectious diseases cancer metabolic disorders

autoimmunity and inflammatory conditions The cytokinesare important for parasitic control and are involved in thegenesis of lesions [97]

It is known that the production of some cytokines isunder genetic control and is influenced by polymorphisms inseveral cytokine genes SNPs ormicrosatellitesmainly locatedin regulatory regions may affect gene transcription and causeinterindividual variations Some of these polymorphismsinfluence the level of cytokine production which can conferflexibility in the immune response [98ndash101] Thus the pres-ence of certain alleles may influence the course of bacterialand viral infections [102 103] and confer susceptibility orresistance to autoimmune disease [104] SNPs in cytokinegenes have been described as important genetic factors in theoccurrence of different clinical forms of Chagas disease The

8 BioMed Research International

genetic susceptibility of single nucleotide polymorphisms incytokine genes to human Chagas disease was reviewed [105]The cytokines polymorphisms associatedwithChagas diseaseare summarized in Table 2

Proinflammatory cytokines play a key role in the develop-ment of CCC Aiming to investigate the influence of theTNF polymorphisms on Chagas disease TNFA (posi-tions minus308 rs1800629 minus244 rs673 minus238 rs361525 andminus1031 rs1799964) and TNFB genotypes have been inter-rogated No significant differences were observed withthese alleles or haplotypes between patients and controls in aPeruvian population [106]TNF-308A alsowas not associatedwith CCC in Brazilian patients [107] However the sameSNP could be directly involved in the genetic susceptibilityof the chronic phase and CCC in a Mexican population[108] Another study also in Brazilian patients suggestedthat allele TNF-238A which correlates with production ofsignificantly higher levels of TNF-120572 could influence thesusceptibility to infection [109] The TNF-1031C and -308Aalleles were significantly associated with the development ofCCC whereas the TNF-1031TT and -308GG genotypes wereassociated with lower risk to develop CCC in a Colombianpopulation [110] Regarding the TNF gene microsatellite tenalleles were associated with Chagas disease in the Brazilianpopulation eight of them correlate with susceptibility(TNFa2 TNFa7 TNFa8 TNFb2 TNFb4 TNFd5 TNFd7and TNFe2) and two with protection (TNFb7 and TNFd3)against the development of the disease [111] Previously theoccurrence of the TNFa2 microsatellite was correlated withreduced survival in severe cardiomyopathy [112] Despite thecontroversial results these data suggest the involvement ofTNF in the course of Chagas disease

Clinical genetic and epidemiological studies have linkedlymphotoxin-120572 (LTA) a proinflammatory cytokine to coro-nary artery disease and myocardial infarction In BrazilianCCC patients homozygosity with respect to the LTA+80C(rs2239704) and LTA+252G (rs909253) alleles was signifi-cantly more frequent and was associated with susceptibil-ity and the haplotype LTA+80A+252A was associated withprotection against CCC Furthermore homozygosity for theLTA+80A allele correlated with the lowest levels of plasmaticTNF-120572 [113]

It appears that IL6 gene polymorphism does not con-tribute to susceptibility in the clinical manifestations ofChagas disease In a study in two independent populationsof Colombia and Peru no difference was observed for IL6-174GC (rs1800795) between Chagas disease and controls orbetween asymptomatic patients and CCC [114]

Some IL1B alleles and haplotypes have been associatedwith susceptibility to inflammatory autoimmune and infec-tious diseases The IL1B-511(rs16944) IL1F103 (rs3811058)IL1RN4 (rs419598) IL1RN 61 (rs315952) and IL-1RN 62(rs315951) polymorphisms were analysed in Chagas diseaseand IL-1RN4CC genotype was clearly associated with Tcruzi infection and CCC development [115] The IL1B+5810G(rs1143633) allele and the haplotype IL1B-31 (rs1143627)+3954(rs1143634)CT were associatedwith an increased risk of CCC[116] Therefore these studies suggest that IL1 gene clusterpolymorphisms may play a relevant role in the susceptibility

to development of CCC and that the effect of IL1B gene onchagasic cardiomyopathy predisposition is dose dependent[116]

IL-10 and INF-120574 production by T cells promotes T cruzicontrol and protects against fatal acute myocarditis [115ndash118]The SNP IL10-1082 (rs1800896) A allele which is associatedwith a lower expression of IL-10 had higher frequency inCCC Brazilian patients when compared to the asymptomaticgroup [119]However inColombian patients no differences inallele frequency and haplotype of the IL10 genewere observedin symptomatic and asymptomatic patients [120] Linkagedisequilibrium analysis on microsatellite loci suggests epis-tasis between MHC and IL-10 on Chagas disease suscep-tibilityresistance [121] The frequency of the IFNG+874AA(rs62559044) which is associated with reduced productionof INF-120574 was increased in the Colombian patients suggestingthat this SNP may be involved in susceptibility but not in theprogression of Chagas disease [122]

IL-4 is described as a prototypical anti-inflammatorycytokine It can modulate the host and parasite survivals thatdepend on a fine balance betweenTh1 responses on one handit will control parasitism and on the other hand enhanceheart inflammation throughout the course of the infection[123] In a Bolivian population SNP IL4-590 (rs2243250)T allele was associated with protection against T cruziinfection [124] although in another study only the IL4RA(IL-4 receptor-120572 rs147781) +148AA genotype showed a weakassociation with the development of CCC [120]

TGF-120573 plays a pivotal role in Chagas disease not onlyin the development of chagasic cardiomyopathy but also inmany stages of the T cruzi life cycle and survival in the hostcell environment through regulation of (i) parasite invasionof heart cells (ii) an intracellular parasite cycle (iii) inflam-mation and immune response (iv) heart fibrosis and remod-elling and (v) gap junction modulation and heart conduc-tion [125] Several SNPs in the TGFB1 gene that may affectcytokine production have been described A significant dif-ference in the distribution of the TGFB1 10 (rs1982073) T andC alleles between patients and healthy controls was observedin the Peruvian and Colombian populations TGFB1 10CCthe high producer genotype was increased in patients of bothpopulations [126]

The IL-12 family of cytokines can influence Th17 andthe production of IL-17 and INF-120574 The SNPs rs3212227 inthe 31015840UTR of the gene IL12B were investigated and IL12B31015840UTR C allele and CC genotype were significantly increasedamong CCC patients when compared to asymptomatic indi-viduals [127]

MIF (macrophage migration inhibitory factor) minus173Callele and CC genotype were related to the major risk ofChagas disease in the Colombian and Peruvian populations[128]

Some chemokines also had been associated with thedevelopment of CCC CXCL9 CC (rs10336) and CXCL10GG (rs3921) genotypes were less frequent and CCR5 CC(rs1799988) was more frequent in patients with left ven-tricular dysfunction compared with patients without thisdysfunction and may indicate that CXCL9 and CXCL10 aremaster regulators of myocardial inflammatory cell migration

BioMed Research International 9

perhaps affecting clinical progression to the life-threateningform of CCC [129] Some SNPs of CCR5 gene were associ-ated with the development of severe cardiomyopathy in anendemic area of Colombia Peru and Venezuela [130ndash132]

In the Brazilian population BAT1 (HLA-B associatedtranscript 1) C allele and CC genotype at positions 22 CGand minus348 CT were associated with risk of cardiomyopathy[133] In the same population MCP-1 (monocyte chemo-attractant protein-1) geneCCL2-2518A allele (rs1024611) andthe CCL2-2518 AA genotype correlate with susceptibility tochronic cardiomyopathy [134] BAT1 MCP-1 and LTA maybe involved in the pathogenesis of cardiac Chagas disease

Despite the controversial results these data suggest theinvolvement of cytokines in the course of Chagas diseaseThebalance between TH1TH2T regulatory cytokines has differ-ent and opposing influences on the likelihood of infectionwith T cruzi and on the clinical course of the Chagas disease

3 Concluding Remarks

Many genetic linkages and association studies have attemptedto identify genetic variations that are involved in immuno-pathogenesis of Chagas disease However causal genetic vari-ants underlying susceptibility remain unknown due to com-plexity of parasite and host Susceptibilityresistance to Cha-gas disease involves multiple genetic variants functioningjointly each with small or moderate effects Immunologicalmechanisms protect against the disease but contribute toaggression and tissue damage Genome wide associationstudies (GWAS) and next generation sequencing (NGS) atpresent lacking in Chagas disease may help identifying novelgenetic polymorphisms with genome scale associations

The impact of pathogens on host cell functions as wellas genetic markers that were significantly associated withdisease was found on schistosomiasis [135] ascariasis [136]leprosy [137] tuberculosis [138 139] malaria [140] dengue[141] hepatitis [142 143] andHIV-1 [144ndash147] In Chagas dis-ease the 2590T allele (rs2243250) polymorphism in the pro-moter region of IL4 gene is a marker for IL4 haplotypes likelyassociated with protection against T cruzi infection [124]

The identification of the specific genes influencing Tcruzi infection and Chagas disease through genome scanstechniques could offer a particular opportunity for mappinggenes of susceptibility or resistance Further studies are neces-sary to clarify the relationship between genotype and devel-opment of disease and its clinical outcomes

The characterisation of the susceptibility genes and theirvariants has important implications not only for a betterunderstanding of disease pathogenesis but also for the con-trol and development of new therapeutic strategies for infec-tious diseases

References

[1] C Chagas ldquoNova tripanozomiaze humana Estudos sobre amorfologia e o ciclo evolutivo do Schizotrypanum cruzi n genn sp Agente etiologico Agente etiologico de uma nova entidademorbida para o homemrdquoMemorias do Instituto Oswaldo Cruzvol 1 pp 159ndash218 1909

[2] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[3] L O Andrade C R S Machado E Chiari S D J Penaand A M Macedo ldquoDifferential tissue distribution of diverseclones of Trypanosoma cruzi in infected micerdquo Molecular andBiochemical Parasitology vol 100 no 2 pp 163ndash172 1999

[4] World Health Organization (2012) Chagas disease (Americantrypanosomiasis) Fact Sheet No 340

[5] L V Kirchhoff ldquoChanging epidemiology and approaches totherapy for Chagas diseaserdquo Current Infectious Disease Reportsvol 5 no 1 pp 59ndash65 2003

[6] C Hoare ldquoThe trypanosomes of mammalsrdquo Journal of SmallAnimal Practice vol 13 pp 671ndash672 1972

[7] C J Schofield ldquoOverview evolution of the triatominaerdquo in Pro-ceedings of the 2nd International Workshop on Population Gen-etics and Control of Triatominae C J Schofield and C PonceEds INDRE Tegucigalpa Honduras 1998

[8] F Rothhammer M J Allison L Nunez V Standen and BArriaza ldquoChagas disease in pre-Columbian South AmericardquoAmerican Journal of Physical Anthropology vol 68 no 4 pp495ndash498 1985

[9] J R Coura ldquoChagas disease what is known and what isneededmdasha background articlerdquoMemorias do Instituto OswaldoCruz vol 102 no 1 pp 113ndash122 2007

[10] A C Aufderheide W Salo M Madden et al ldquoA 9000-yearrecord of Chagas diseaserdquo Proceedings of the National Academyof Sciences of USA vol 101 no 7 pp 2034ndash2039 2004

[11] Y Carlier J C PDias AO LuquettiMHonteberye F Torricoand C Truyens ldquoTrypanosomiase americaine ou maladie deChagasrdquo in Encyclopedie Medico Chirurgicale Elsevier ParisFrence 2002

[12] W B Bean ldquoThe illness of Charles DarwinrdquoTheAmerican Jour-nal of Medicine vol 65 no 4 pp 572ndash574 1978

[13] F Koberle ldquo50 Years of Chagasrsquo diseaserdquoMunchener Medizinis-che Wochenschrift vol 99 pp 1193ndash1198 1957

[14] A Moncayo and M I Ortiz Yanine ldquoAn update on Chagasdisease (humanAmerican trypanosomiasis)rdquoAnnals of TropicalMedicine and Parasitology vol 100 no 8 pp 663ndash677 2006

[15] G A Schmunis ldquoEpidemiology of Chagas disease in non-ende-mic countries the role of internationalmigrationrdquoMemorias doInstituto Oswaldo Cruz vol 102 no 1 pp 75ndash85 2007

[16] G A Schmunis and Z E Yadon ldquoChagas disease a LatinAmerican health problem becoming a world health problemrdquoActa Tropica vol 115 no 1-2 pp 14ndash21 2010

[17] J R Coura and P A Vinas ldquoChagas disease a new worldwidechallengerdquo Nature vol 465 no 7301 pp S6ndashS7 2010

[18] A F Henao-Martınez D A Schwart and I V Yang ldquoChagasiccardiomyopathy from acute to chronic is this mediated byhost susceptibility factorsrdquo Transactions of the Royal Society ofTropicalMedicine andHygiene vol 106 no 9 pp 521mdash527 2012

[19] D P Neves A L Melo and O Genaro Eds ParasitologiaHumana Atheneu Sao Paulo Brazil 2005

[20] D Born R E S Acha and M Ferraz ldquoPregnancy and Chagasrsquodiseaserdquo Journal of the American College of Cardiology vol 31p 421 1998

[21] E L P Camandaroba C M Pinheiro Lima and S G AndradeldquoOral transmission of Chagas disease importance of Trypano-soma cruzi biodeme in the intragastric experimental infectionrdquoRevista do Instituto de Medicina Tropical de Sao Paulo vol 44no 2 pp 97ndash103 2002

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

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Molecular Biology International

GenomicsInternational Journal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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BioinformaticsAdvances in

Marine BiologyJournal of

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Signal TransductionJournal of

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Evolutionary BiologyInternational Journal of

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ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Microbiology

Page 2: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

2 BioMed Research International

human populations in pre-Columbian times [8] Howeverthe establishment of Chagas disease itself as a zoonosisoccurred 200ndash300 years ago as a result of deforestationcaused by the expansion of agriculture and livestock whenhumans approached the natural invertebrate niches [9]

There are indications that human infection with T cruzihas occurred since at least nine thousand BC years in popu-lations of the Andean countries it was possible to identifymolecular remnants of T cruzi in mummies of these era andregion [10] and Peruvian ceramics dating from the thirteenthto sixteenth centuries revealed possible representations ofChagas disease including a head with unilateral ocularoedema identical to the Romana signal that often characte-rises the context of acute infection [11]

Charles Darwin observed the behaviour of the triatomineinsect transmitter during his passage through Argentina andwrote in his diary ldquoTheVoyage of the Beaglerdquo that he had beenbitten by the same insect while visiting Chile in 1835The pre-sence of gastric symptoms and his final death caused by heartproblems in 1882 was suggested to be due to Chagas disease[12]

The disease was described for the first time in 1907 whenCarlos Chagas described the trypanosome the transmissioninsect and the syndrome that characterised a new tropicalparasitic disease [1 13]

13 Epidemiology It is estimated that 10 million people areinfectedwithT cruziworldwidemostly in LatinAmerica [4]and about 100 million people are at risk of the disease in theAmericas with a total estimated incidence of 800000 newcases per year [14]

Chagas disease was characterised as a neglected disease ofpoor and rural populations but the progressive urbanisationespecially since the 1940 has made the disease an urbanproblem of medical and social importance The disease hasalso spread from Latin America to nonendemic countrieswith the movements of people from endemic to nonendemiccountries including North America Western Pacific regions(mainly Australia and Japan) and Europe It is estimated thattoday there are over 300000 individuals infectedwithT cruziin the United States over 5500 in Canada over 80000 inEurope and the Western Pacific region more than 3000 inJapan and more than 1500 in Australia [15ndash18] Thus theprevalence incidence and mortality associated with Chagasdisease showed considerable variations in recent decadesmainly due to the impact of control programs migrationof rural and urban populations and socioeconomic changes[14] Although the estimates of prevalence of infection aregradually decreasing the disease still exists

14 Transmission of Chagas Infection The transmission ofChagas infection can be divided into primary and secondarymechanisms the main mechanisms include transmissionthrough insect vectors by blood transfusion contaminatedfood and congenital transmission Secondary mechanismtransmissions may occur by laboratory accidents organtransplants sexual transmissionwounds in contactwith con-taminated sperm or menstrual fluid and hypothetically by

inoculation by criminal or deliberate contamination of foodwith the parasite [9]

The diseasersquos reservoir lies in 100 different mammalspecies of wild animals It is transmitted by several dozens ofinsect species belonging to the family Reduviidae subfamilyTriatominaeThese insects hide in wild animalsrsquo nests or lairsand extract their bloodmeals (wild cycle) In the insect vectorthe trypanosome undergoes several and successive develop-mental stages terminating as a flagellated form that staysin the vectorrsquos rectum At night humans are bitten by theseinsects usually in the facial area (domestic cycle) Ingestion ofthe bloodmeal causes the vector to defecate After awakeningthe victim usually rubs the bite area and pushes the stool withthe trypanosome into the wound or onto the conjunctivaAfter the T cruzi accesses the victimrsquos blood this initiates theacute phase of the disease Widely distributed via the bloodstream the trypanosome sheds its flagellum and penetratestissue cells They proliferate by binary fission within the cells(especially myocardium and meninges) [19]

Transfusion infection is the second most importantepidemiological mechanism in the transmission of Chagasdisease [19] In 1960 theWorld Health Organization (WHO)estimated seven million cases per year due to blood trans-fusions in Latin America and this finding helped changepolicy and practice [14 15] Congenital transmission istransplacental and seems to depend on factors related tothe parasite and the host trypomastigotes penetrate theplacenta through the chorionic epithelium and trophoblasticHofbauer cells (macrophages placenta) where they transforminto amastigotes [20] Oral transmission of Chagas diseasecan occur especially associated with contamination of breastmilk (congenitally) fruit juices and vegetables contaminatedby infected wild vectors [21]

Other forms of exceptional transmission can occur Acci-dents involve researchers and laboratory technicians workingwith the parasite through the blood of infected people andanimals culture media or vector The transmission by coitushas never been proven in humans there are only reportsof trypomastigotes in the blood of menstruation chagasicwomenThe presence of trypomastigotes was found in spermfrom experimentally infected mice and infection was alsodemonstrated after depositing T cruzi in the vagina of rats[19]

15 Clinical Manifestations and Diagnosis Human T cruziinfection evolves from a usually oligosymptomatic acutephase to a chronic disease The biological and genetic vari-ability of the parasite and of the hostmay influence the courseof disease progression [3 22]

The early or acute phase of infection is characterisedby high parasitaemia or trypomastigote circulating forms inthe blood for two to four months [23] During this periodthe mortality ranges from 5 to 10 due to episodes ofmyocarditis and meningocefalite [24 25] The clinical signsassociated with infection are a local inflammatory reactionwith formation of strong swelling in the region of entry of theparasite (chagoma or Romana sign) fever splenomegaly andcardiac arrhythmia [26] The presence of circulating para-sites can be detected by xenodiagnosis haemoculture [27]

BioMed Research International 3

and molecular characterisation of the parasitersquos DNA by thepolymerase chain reaction (PCR) [28] During the acutephase the majority of infected individuals develop a humoraland cellular immune response responsible for the decrease ofparasites in the blood

After that the patients progress to the chronic asymp-tomatic stage that affects most individuals (50 to 60)this condition characterises the indeterminate clinical form(IND) of the disease and it may remain for long periodsof time [23 27] About 20 to 30 develop cardiomyopa-thy that reflects a myocardium progressively damaged byextensive chronic inflammation and fibrosis and in terminalphases usually presents as dilated cardiomyopathy ChronicChagas cardiomyopathy (CCC) is the most relevant clinicalmanifestation causing death from heart failure in endemiccountries and accounts for a significant burden of ischaemicand inflammatory heart diseases in the USA and Europe dueto ldquoglobalisationrdquo of Chagas disease Eight to 10 has thedigestive form characterised by dilation of the oesophagus orcolon (megaoesophagus andmegacolon) Some patients haveassociated cardiac and digestivemanifestations known as themixed or cardiodigestive form [17 29 30]

The transition from acute to chronic phase is accom-panied by a marked decrease in parasitaemia due to themounting of a relatively effective immune response whichkeeps parasite frequency at below detectable levels in thehost To diagnose the disease regardless of stage the sero-logical test is used by detecting antibodies specific to theparasite IgM (acute phase) and IgG (indeterminate andchronic phase) [31] Conventional serological tests includeprimarily immunofluorescence assays (IFA) enzyme-linkedimmunosorbent assays (ELISA) and indirect haemaggluti-nation assays (IHA)These tests were summarised by Afonsoet al [32] Changes in the chronic phase can be revealed byelectrocardiogram clinical diagnosis X-rays and ultrasound[27 33]

16 Host Immune Response There is a consensus that duringT cruzi infection the host immune system induces complexprocesses to ensure the control of parasite growth Theimmune response is crucial for protection against diseasehowever immunological imbalances can lead to heart anddigestive tract lesions in chagasic patients Several studieshave evaluated the innate cellular and humoral immuneresponses in chagasic patients in an attempt to correlateimmunological findings with clinical forms of Chagas dis-ease However in all clinical forms of Chagas disease theinvolvement of cell-mediated immunity is undoubtedly ofmajor importance [34ndash36]

It is also accepted that T cruzi induces a strong activationof the immune system during acute infection and that thedifferent immunological mechanisms triggered during theearly indeterminate stages of the infection may representan essential component of the immune activity observedduring ongoing clinically distinct chronic infection Afterinvasion of infectious metacyclic trypomastigotes in themammalian host T cruzi infects a variety of cell types suchas macrophages and fibroblasts Fibroblasts are numerousin the extracellular matrix of the skin and are refractory

to apoptosis [37] unlike macrophages and cardiomyocytesInfected macrophages initiate the molecular interactions thatmobilise the innate immune response of the host by sec-retion of proinflammatory cytokines like tumour necrosisfactor alpha (TNF-120572) and interleukin- (IL-) 12 [38] Thesecytokines activate Natural Killer (NK) cells to produce inter-feron-gamma (IFN-120574) that acts directly on macrophagesactivating them for antimicrobial activity Activated macro-phages produce nitric oxide (NO) via NO synthase (iNOSNOS2) potent against T cruzi Furthermore the regulatorycytokinesmdashIL-4 IL-10 and transforming growth factor beta(TGF-120573)mdashinhibit the production of NO and trypanocidalactivity of activated macrophages is responsible for disablingthe control of lethal inflammatory effects of type 1 cytokinesproduced during infection [39]

Uncontrolled activation of NK cells andmacrophages canlead to tissue damage According to Vitelli-Avelar et al [40]there is a mixed profile of cytokine production and highlevels of IFN-120574 TNF-120572 and IL-4 favour the generation ofinflammatory mechanisms This intense inflammatory pro-cess during the initial infection is essential to confine the aeti-ologic agent in the intracellular site (limiting infection andsymptoms) and prevent tissue damage but can be determin-ant to immunopathology

The lesions of the acute phase of the disease are charac-terised by the presence of localised inflammatory reactionswith a predominance of mononuclear cells at the foci ofthe pseudocyst ruptures occasionally with the formation ofgranulomas located mainly in muscle and cardiac tissue [17]

There is a robust immune response displayed in the INDdespite the complete lack of clinical disease Many studiesconcerning the cellular immune response in the IND havebeen performed Peripheral blood cells from these patientsproliferate when stimulated with antiepimastigote antibodies[35] Analysis of the expression of activation markers by T-cells showed that INDpatients have a high frequency of CD4+and CD8+ T-cells expressing HLA-DR and CD45RO [33]Moreover the vastmajority of these T-cells do not express thecostimulatory molecule CD28 [35] which suggested that thissubpopulation displayed down-modulatory activity due tointrinsic regulation via CTLA-4 In mice deficiency in eitherclass I- or class II-restricted T-cell populations was observedas a striking similarity in their mortality rate [41] Given thatCD8+ T-cells seem to be the best candidate for tissue destruc-tion it is possible that this regulatorymechanism working intandem with others helps prevent pathology in IND [42]

Despite it being considered for decades that the adaptiveimmune response is the most important protective mecha-nism during chronic infection recent studies have suggestedthe importance of the innate response as a regulatory mech-anism for controlling morbidity during disease Monocytesfrom IND patients in vitro lead to a high expression of IL-10 consistent with a modulatory response CD3-D16+CD56+

and CD3minus CD16+ CD56dim NK cells counts are particularlyhigh suggesting a protective role of this cell subpopulationCD56dim NK cells had more cytotoxic activity and can con-tribute to the control of parasitism Added to this asymp-tomatic patients exhibited Treg cells (CD4+CD25high) NKT

4 BioMed Research International

regulatory cells (CD3minusCD56+CD16+) and macrophage-likeregulatory cells (CD14+CD16+) that encourage the establish-ment and maintenance of the IND form [39 43]

CCC is associated with the presence of an intense inflam-matory infiltrate in the myocardium especially at sites whereT cruzi antigens are observed The infiltrate was composedespecially by CD8+ T-cells IL-7 and IL-15 are critical formaintenance of these cells and their activation state in theheart tissue of CCC [44] CD8+ T-cells are also found in thecirculation Similar to what was described in IND patientsCD8+ and CD4+ cells present high expression of HLA-DRand lower expression of CD28 however here CD4+ cellswere correlated with the expression of TNF-alpha [35 36] aswell as IFN-120574 The latter cytokine is higher in CCC than INDpatients andmay be a key factor in the development of severecardiomyopathy [45] Monocytes from cardiac patients alsoproduce TNF-120572 and IL-10 Although cells from CCC patientsare able to produce IL-10 the ratio of this cytokine seems tobe lower in cardiac patients [45]

During the T cruzi-cardiomyocyte interaction the par-asite has control of the host cell gene expression includingexpression of genes related to immune response inflamma-tion cytoskeletal organisation cell-cell and cell-matrix inter-actions apoptosis cell cycle and oxidative stress [46] Theintense production of cytokines chemokines and nitricoxide that are essential elements of the defensive reaction incardiac tissue can also result in cardiac hypertrophyThe acti-vation of the host cell apoptotic machinery by pathogens isan offensive strategy to eliminate the hostrsquos immune response[47]

Megaoesophagus and megacolon are the major causesof morbidity in the digestive clinical form of chronic Cha-gas disease Inflammatory infiltrates and fibrosis are foundassociated with lesions of muscle cells and of the intramuralnervous system They are composed mainly of CD3+CD4+T lymphocytes CD20+ B lymphocytes CD57+ NK cellsand CD68+ macrophage-like cells [48] Correa-Oliveira etal [45] observed that patients with the gastrointestinal formof Chagas disease demonstrated a significant decrease in theabsolute number of CD3+ T-cells as well as in CD19+ Blymphocytes and an inversion of the CD4CD8 ratio con-trastingwith results fromCCCwhere the ratio of these cells isnormal Chagasic patients with megacolon present increasednumbers of eosinophils and mononuclear cells [49] Thesecells are associatedwith inflammatory processes and can con-tribute to tissue injury through the secretion of cytokinessuch as IL-1 TNF-120572 and IL-6 which activate the cytotoxicprocess [50]

17 Pathogenesis in Chagas Disease Based on the relationshipof parasite and host interaction the mechanisms of patho-genesis in human Chagas disease can be based on two mainhypotheses The first defends the pivotal role of parasitersquospersistence in the host as a major cause of pathology whilethe other postulates that an immune response against self-antigens is responsible for the tissue damage observed inaffected organs of chagasic individuals

T cruzi exhibits multiple strategies to ensure its estab-lishment and persistence in the host Although this parasite

has the ability to infect different organs heart impairmentis the most frequent clinical manifestation of the diseaseCalvet et al [47] reviewed the current understanding ofmole-cules involved in T cruzi-cardiomyocyte recognition themechanism of invasion and the effect of intracellular devel-opment of T cruzi on the structural organisation and molec-ular response of the target cell The nature of the myocardialchanges in the chronic stage has been considered by some tobe an autoimmune phenomenon based on antigenicmimicryin the form of an antibody targeting T cruzi polypeptides[51] More recently however persistence of the parasite in thetissues has been demonstrated [52]

Although the theories are controversial autoreactivityand parasite persistence theories are not mutually exclusiveThe variation in pathologicalmanifestation has been reportedand was related to differences in host immune response suchas the ability to control parasitaemia the strength of inflam-matory reactions and the induction of autoimmune-likeresponses [53]

2 Genetic Factors and Their Influence onChagas Disease

The advance in knowledge about infection and disease haschanged the concept of infectious diseases and the geneticmarkers play an important role in this area [54] The spec-trum of expression of Chagas disease brings strong evidenceof the influence of the genetic factors on its clinical course[55]

The polymorphisms of the genes involved in the innateand specific immune response are being widely studied inorder to clarify their possible role in the occurrence or sever-ity of disease To identify possible host genetic factors thatmay influence the clinical course of Chagas disease the roleof classic and nonclassic major histocompatibility complex(MHC) genes killer cell immunoglobulin-like receptor (KIR)genes and cytokine genes that are involved in the immuneresponse will be addressed

21 Strategy for Screening and Selecting Studies This reviewabout genetic factors and their influence on Chagas diseaseselected original articles carried out on humans that werefound in the databases of PubMed (US National Library ofMedicine) LILACs (Latin American and Caribbean Centeron Information in Health Sciences) and Google ScholarTheresearch period covered included the limit of databases untilMarch 2013 There was no restriction regarding languageIn the PubMed database MeSH (Medical Subject HeadingTerms) were used and in the LILACS descriptors wereused In order to retrieve articles of interest free termswere used in the LILACS and Google Scholar The MeSHterms descriptors and free terms were organized accordingto thematic groups (i) HLA and Chagas disease (ldquoChagasDiseasegeneticsrdquo OR ldquoChagas Diseaseimmunologyrdquo ANDldquoHLAAntigensgeneticsrdquoOR ldquoHLA antigensimmunologyrdquo)(ii) MIC and Chagas disease (ldquoChagas diseasegeneticsrdquoAND ldquoMHC class I-related chain Ardquo) (iii) KIR genes andChagas disease (ldquoChagas diseasegeneticsrdquo AND ldquoReceptorsKIRgeneticsrdquo) (iv) Cytokine genes and Chagas disease

BioMed Research International 5

Potentially relevant citations at electronic databases (n = 173)

Citations which failed in the inclusion no human aimoriginality duplicate articles and double data criteria (n = 139)

Potentially relevant articles for analysis related to immuneresponse genes in association with Chagas disease (n = 34)

Articles which were added from reference list (n = 6)

40 original articles on human infections included in this review

Figure 1 Flow chart of the study for review

(ldquoChagas diseasegeneticsrdquo AND ldquocytokinesgeneticsrdquo ORldquoChemokinesgeneticsrdquo OR ldquoReceptors cytokinegeneticsrdquoThe immune response genes as HLA KIR MIC and cyto-kines and their association with Chagas disease and its clin-ical forms in the American Latin population were presentedThe results were summarized in Figure 1 and the selectedstudies are presented in Tables 1 and 2

22 HLA and Chagas Disease To identify possible host gen-etic factors that may influence the clinical course of Chagasdisease the molecules and genes in the region of the humanleucocyte antigen (HLA) have been analysed in patientspresenting with differing clinical symptoms

The highly polymorphic HLA class I (A B and C) andII (DR DQ and DP) molecules determine the efficiency ofpresentation of the T cruzi epitopes to CD8+ and CD4+ T-cells respectively The type of the presentation could affectthe clinical course of diseases because patients may responddifferently to the same antigen depending on their HLArepertory [56]

HLA alleles and haplotypes associated with Chagas dis-ease are summarized in Table 1

Several HLA alleles and haplotypes have been reportedto be associated with Chagas disease In Venezuela a studycomparing class II allele frequencies between patients andcontrols identified a decreased frequency of DRB1lowast14 andDQB1lowast0303 in patients suggesting independent protectiveeffects to chronic infection in this population In thissame study a higher frequency of DRB1lowast01 DRB1lowast08 andDQB1lowast0501 and a decreased frequency of DRB1lowast1501 werefound in patients with arrhythmia and congestive heartfailure [57] In an endemic area of central Venezuela a higherfrequency of the HLA-DPB1lowast0401 allele and DPB1lowast0401-HLA-DPB1lowast2301 or DPB1lowast0401-DPB1lowast3901 haplotype was

found in patients with cardiac manifestations [58] Sus-ceptibility between HLA-Clowast03 and CCC Venezuelan wasconfirmed [59]

In Chile HLA-B40 antigen in the presence of Cw3 wassignificantly lower in subjects with CCC [60] and was foundin higher expression in patients without evidence of heartdisease in Santiago [61]

An increase of HLA-A31 B39 and DR8 and a decreaseof HLA-DR4 DR5 DQ1 and DQ3 were observed in severalLatin American mestizos from different countries and withCCC [62]

A study in south-eastern Brazil showed that HLA-Alowast30was involved in susceptibility to Chagas disease whereasHLA-DQB1lowast06 was related to protection regardless of theclinical form of the disease [63] and HLA-DR2 was asso-ciated with susceptibility to chronic Chagas disease in asouth Brazilian population [64] However in another studythe polymorphism of HLA-DR and -DQ does not influencethe susceptibility to different clinical forms of Chagas dis-ease or the progression to severe Chagasrsquo cardiomyopathy[65]

The haplotype HLA-DRB1lowast14-DQB1lowast0301 was involvedin resistance to infection with T cruzi in a rural mestizopopulation of southern Peru [66]

In the Mexican population HLA-DR4 and HLA-B39were associated with the infection by the T Cruzi whereasHLA-DR16 was a marker of susceptibility to damage tothe heart and HLA-A68 was related with protection todevelopment of CCC [67]

In Argentina the class II allele HLA-DRB1lowast0409 andDRB1lowast1503 was significantly more prevalent in Chagas dis-ease and DRB1lowast1103 allele was associated with disease resist-ance Increased frequency of DRB1lowast1503 allele was foundamong CCC suggesting susceptibility [68 69]

In Bolivia the frequencies of HLA-DRB1lowast01 and HLA-Blowast1402 were significantly lower in patients suffering frommegacolon as well as in those with ECG alteration andormegacolon compared with a group of IND patientsThe DRB1lowast0102 Blowast1402 and MICAlowast011 alleles were instrong linkage disequilibrium and the HLA-DRB1lowast01-Blowast14-MICAlowast011 haplotype was associated with resistance againstchronic Chagas disease [70]

These different results between the HLA allele and hap-lotypes and Chagas disease could be caused by variability ofHLA allelersquos distribution in different ethnic groups the typingtest (serological or molecular techniques) the methods ofstatistical analyses (simple chi-square test and logistic orlinear regression) and interpretation (119875 value or 119875

119888value that

applies the Bonferroni correction for multiple comparisons)the selection of the patients and the clinical form the num-bers of individuals linkage disequilibrium and biologicalvariability of the parasite Nevertheless genetic factors relatedto the HLA system reflect an important role in susceptibilityor protection to Chagas disease and its clinical forms

23 MIC and Chagas Disease The HLA region containsnot only classical HLA genes but also a wide variety ofimmunologically relevant genes such as nonclassical class Igenes (MICAMICB major histocompatibility complex class

6 BioMed Research International

Table 1 Alleles and haplotypes HLA associated with Chagas disease

HLA class I alleles andhaplotypes

HLA class II alleles andhaplotypes Population Clinical forms Association Reference

aDRB1lowast01 DQB1lowast0303 Venezuela Chronic phase Protection [57]aDRB1lowast1501 CCC Protection [57]aDRB1lowast08 CCC Susceptibility [57]aDRB1lowast01 DQB1lowast0501 CCC Susceptibility [57 58]aDPB1lowast0401aDPB1lowast0401ndashlowast2301aDPB1lowast0401ndashlowast3901 haplotypes CCC Susceptibility [58]

bClowast03 CCC Susceptibility [59]aHLA-B40-Cw3 haplotype Chile CCC Protection [60 61]bHLA-Alowast30 Brazil All clinical form Susceptibility [63]

bDQB1lowast06 All clinical form Protection [63]bDR2 Chronic phase Susceptibility [64]

No association [65]bDRB1lowast14-DQB1lowast0301 haplotype Peru Infection Protection [66]

bHLA-B39 bHLA-DR4 Mexico Infection Susceptibility [67]bHLA-B35 bHLA-DR16 CCC SusceptibilitybHLA-A68 CCC Protection

bDRB1lowast0409 and lowast1503 Argentina Infection Susceptibility [68 69]bDRB1lowast1103 Infection Protection [69]bDRB1lowast1503 CCC Susceptibility [69]

bHLA-Blowast1402 bHLA-DRB1lowast01 Bolivian DG or mixed Protection [70]bHLA-DRB1lowast01-Blowast14-MICAlowast011haplotype Infection Protection [70]

bHLA-B35-MICA-A5haplotype Guatemala CCC Susceptibility [79]

bA31 and B39 bDR8 Latin American mestizos CCC Susceptibility [62]bDR4 DR5 DQ1 DQ3 CCC Protection

a119875 value le 005 or b

119875119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

I chain-related genes A and B) thatmay be involved in diseasepathogenesis

TheMICAmolecules are recognised by lymphocytes T120574120575lymphocytes T120572120573 CD8+ and NK cells via their receptorsNKG2D present on their surfaces in association with theDAP10 molecule an adapter protein membrane [71 72] Thiscomplex NKG2D-MICA activates the phosphorylation oftyrosine residues of themolecule DAP10 triggering a cascadeof cell signalling that ends with the process of cell lysis of thetarget cells [72] A study by Steinle et al [73] showed thatchanging a single amino acidmdasha methionine for a valine atposition 129 of the1205722 domain of the heavy chainmdashcategorisesthe MICA as strong (MICA-129met) and weak (MICA-129val) ligands of NKG2D affecting the activation of NK cells

MICA and MICB are weakly expressed on healthy cellsbut their expression is induced in response to cellular stressin many cell types including epithelial cells fibroblastskeratinocytes endothelial cells and monocytes [74ndash77]

The polymorphism of MICA may be involved in sus-ceptibility to various diseases but it has been suggestedthat this association may be secondary due to the strong

linkage disequilibrium with HLA-B alleles Groh et al [78]found that MICAlowast011 which was closely linked to HLA-Blowast14 and DRB1lowast01 might stimulate T120574120575 cells in the gutmucosa a phenomenon that could relate to megacolonIn Chagas disease the same HLA-DRB1lowast01-Blowast14-MICAlowast011haplotype was associated with resistance against the chronicform [70] MICA-A5 and HLA-B35 synergistically enhancedsusceptibility to CCC [79]

24 Association of KIR Genes and Their HLA Ligands withChagas Disease Other receptors of NK cells that recogniseHLA class I molecules present on the target cells includedKIR (killer cell immunoglobulin-like receptor) [80 81] KIRreceptors are glycoproteins that belong to the immunoglobu-lin superfamily and which are also found in some subpopu-lations of T-cells [82] KIR genes are clustered in the 19q134region and are characterised by both allelic (high numbersof variants) and haplotypic (different numbers of genes forinhibitory and activating receptors on individual chromo-somes) polymorphismsThe specific KIR-HLA combinationsmay regulate NK cell-mediated immunity against infectious

BioMed Research International 7

Table 2 Polymorphisms in cytokines genes and their association with Chagas disease

Geneallelegenotype Population Clinical form Association ReferenceTNFA minus308 minus244 minus236and TNFB Peru Infection and CCC No association [106]

bTNF minus308A Mexico Infection and CCC Susceptibility [108]TNF minus308A Brazil CCC No association [107]aTNF minus238A Brazil Infection Susceptibility [109]aTNF minus1031C and minus308A Colombia CCC Susceptibility [110]aTNFA minus1031TT andminus308GG Colombia CCC Protection [110]aTNFa2 TNFa7 TNFa8TNFb2 TNFb4 TNFd5TNFd7 TNFe2

Brazil CCC DG or mixed Protection [111]

aTNFb7 and TNFd3 Brazil CCC and mixed Susceptibility [111]aTNFa2 Brazil CCC Susceptibility [112]bLTA +80C and LTA +252G Brazil CCC Susceptibility [113]bLTA +80A +252Ahaplotype Brazil CCC Protection [113]

IL6 minus174GC PeruColombia Infection No association [114]bIL minus1RN4CC Mexico CCC Susceptibility [115]bIL1B +5810G allele andIL1B minus31 +395 CT genotype Colombia CCC Susceptibility [116]

aIL10 minus1082A and minus1082AA Brazil CCC Susceptibility [119]IL10 Colombia Infection No association [120]aIFNG +874A and +874AA Colombia Infection Susceptibility [122]aIL4 minus590T Bolivia Infection Protection [124]aIL4RA +148AA CCC Susceptibility [120]aTGFB110C and CC PeruColombia Infection Susceptibility [126]bIL12B 31015840 UTR C and CC Colombia CCC Susceptibility [127]aCXCL9CC and CXCL10GG Brazil CCC Protection [129]CCR5CC CCC Susceptibility [129]abCCR5 minus2554T minus2733G59029G 59029AG59029GG

PeruColombiaVenezuela CCC Susceptibility [130ndash132]

aCCL2 minus2518A and AA Brazil CCC Susceptibility [133]aBAT1 22C 348C Brazil CCC Susceptibility [134]a119875 value le 005 b119875

119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

pathogens and contribute to diverse susceptibility to diseasesand other clinical situations

Several studies have shown the participation ofKIR genesand their ligands in infectious diseases [83ndash89] autoimmuneor inflammatory diseases [90ndash92] cancer [93ndash95] and in thesuccess of transplantation [96] However there are no dataavailable on the role ofKIR genes in the immunopathogenesisof Chagas disease

25 Association of Polymorphisms in Cytokine Genes withChagas Disease Immunomodulatory cytokines secreted byT-cells and macrophages are molecules that act as mediatorsof inflammation and immune response These moleculesare key components in the pathogenesis of many diseasesincluding infectious diseases cancer metabolic disorders

autoimmunity and inflammatory conditions The cytokinesare important for parasitic control and are involved in thegenesis of lesions [97]

It is known that the production of some cytokines isunder genetic control and is influenced by polymorphisms inseveral cytokine genes SNPs ormicrosatellitesmainly locatedin regulatory regions may affect gene transcription and causeinterindividual variations Some of these polymorphismsinfluence the level of cytokine production which can conferflexibility in the immune response [98ndash101] Thus the pres-ence of certain alleles may influence the course of bacterialand viral infections [102 103] and confer susceptibility orresistance to autoimmune disease [104] SNPs in cytokinegenes have been described as important genetic factors in theoccurrence of different clinical forms of Chagas disease The

8 BioMed Research International

genetic susceptibility of single nucleotide polymorphisms incytokine genes to human Chagas disease was reviewed [105]The cytokines polymorphisms associatedwithChagas diseaseare summarized in Table 2

Proinflammatory cytokines play a key role in the develop-ment of CCC Aiming to investigate the influence of theTNF polymorphisms on Chagas disease TNFA (posi-tions minus308 rs1800629 minus244 rs673 minus238 rs361525 andminus1031 rs1799964) and TNFB genotypes have been inter-rogated No significant differences were observed withthese alleles or haplotypes between patients and controls in aPeruvian population [106]TNF-308A alsowas not associatedwith CCC in Brazilian patients [107] However the sameSNP could be directly involved in the genetic susceptibilityof the chronic phase and CCC in a Mexican population[108] Another study also in Brazilian patients suggestedthat allele TNF-238A which correlates with production ofsignificantly higher levels of TNF-120572 could influence thesusceptibility to infection [109] The TNF-1031C and -308Aalleles were significantly associated with the development ofCCC whereas the TNF-1031TT and -308GG genotypes wereassociated with lower risk to develop CCC in a Colombianpopulation [110] Regarding the TNF gene microsatellite tenalleles were associated with Chagas disease in the Brazilianpopulation eight of them correlate with susceptibility(TNFa2 TNFa7 TNFa8 TNFb2 TNFb4 TNFd5 TNFd7and TNFe2) and two with protection (TNFb7 and TNFd3)against the development of the disease [111] Previously theoccurrence of the TNFa2 microsatellite was correlated withreduced survival in severe cardiomyopathy [112] Despite thecontroversial results these data suggest the involvement ofTNF in the course of Chagas disease

Clinical genetic and epidemiological studies have linkedlymphotoxin-120572 (LTA) a proinflammatory cytokine to coro-nary artery disease and myocardial infarction In BrazilianCCC patients homozygosity with respect to the LTA+80C(rs2239704) and LTA+252G (rs909253) alleles was signifi-cantly more frequent and was associated with susceptibil-ity and the haplotype LTA+80A+252A was associated withprotection against CCC Furthermore homozygosity for theLTA+80A allele correlated with the lowest levels of plasmaticTNF-120572 [113]

It appears that IL6 gene polymorphism does not con-tribute to susceptibility in the clinical manifestations ofChagas disease In a study in two independent populationsof Colombia and Peru no difference was observed for IL6-174GC (rs1800795) between Chagas disease and controls orbetween asymptomatic patients and CCC [114]

Some IL1B alleles and haplotypes have been associatedwith susceptibility to inflammatory autoimmune and infec-tious diseases The IL1B-511(rs16944) IL1F103 (rs3811058)IL1RN4 (rs419598) IL1RN 61 (rs315952) and IL-1RN 62(rs315951) polymorphisms were analysed in Chagas diseaseand IL-1RN4CC genotype was clearly associated with Tcruzi infection and CCC development [115] The IL1B+5810G(rs1143633) allele and the haplotype IL1B-31 (rs1143627)+3954(rs1143634)CT were associatedwith an increased risk of CCC[116] Therefore these studies suggest that IL1 gene clusterpolymorphisms may play a relevant role in the susceptibility

to development of CCC and that the effect of IL1B gene onchagasic cardiomyopathy predisposition is dose dependent[116]

IL-10 and INF-120574 production by T cells promotes T cruzicontrol and protects against fatal acute myocarditis [115ndash118]The SNP IL10-1082 (rs1800896) A allele which is associatedwith a lower expression of IL-10 had higher frequency inCCC Brazilian patients when compared to the asymptomaticgroup [119]However inColombian patients no differences inallele frequency and haplotype of the IL10 genewere observedin symptomatic and asymptomatic patients [120] Linkagedisequilibrium analysis on microsatellite loci suggests epis-tasis between MHC and IL-10 on Chagas disease suscep-tibilityresistance [121] The frequency of the IFNG+874AA(rs62559044) which is associated with reduced productionof INF-120574 was increased in the Colombian patients suggestingthat this SNP may be involved in susceptibility but not in theprogression of Chagas disease [122]

IL-4 is described as a prototypical anti-inflammatorycytokine It can modulate the host and parasite survivals thatdepend on a fine balance betweenTh1 responses on one handit will control parasitism and on the other hand enhanceheart inflammation throughout the course of the infection[123] In a Bolivian population SNP IL4-590 (rs2243250)T allele was associated with protection against T cruziinfection [124] although in another study only the IL4RA(IL-4 receptor-120572 rs147781) +148AA genotype showed a weakassociation with the development of CCC [120]

TGF-120573 plays a pivotal role in Chagas disease not onlyin the development of chagasic cardiomyopathy but also inmany stages of the T cruzi life cycle and survival in the hostcell environment through regulation of (i) parasite invasionof heart cells (ii) an intracellular parasite cycle (iii) inflam-mation and immune response (iv) heart fibrosis and remod-elling and (v) gap junction modulation and heart conduc-tion [125] Several SNPs in the TGFB1 gene that may affectcytokine production have been described A significant dif-ference in the distribution of the TGFB1 10 (rs1982073) T andC alleles between patients and healthy controls was observedin the Peruvian and Colombian populations TGFB1 10CCthe high producer genotype was increased in patients of bothpopulations [126]

The IL-12 family of cytokines can influence Th17 andthe production of IL-17 and INF-120574 The SNPs rs3212227 inthe 31015840UTR of the gene IL12B were investigated and IL12B31015840UTR C allele and CC genotype were significantly increasedamong CCC patients when compared to asymptomatic indi-viduals [127]

MIF (macrophage migration inhibitory factor) minus173Callele and CC genotype were related to the major risk ofChagas disease in the Colombian and Peruvian populations[128]

Some chemokines also had been associated with thedevelopment of CCC CXCL9 CC (rs10336) and CXCL10GG (rs3921) genotypes were less frequent and CCR5 CC(rs1799988) was more frequent in patients with left ven-tricular dysfunction compared with patients without thisdysfunction and may indicate that CXCL9 and CXCL10 aremaster regulators of myocardial inflammatory cell migration

BioMed Research International 9

perhaps affecting clinical progression to the life-threateningform of CCC [129] Some SNPs of CCR5 gene were associ-ated with the development of severe cardiomyopathy in anendemic area of Colombia Peru and Venezuela [130ndash132]

In the Brazilian population BAT1 (HLA-B associatedtranscript 1) C allele and CC genotype at positions 22 CGand minus348 CT were associated with risk of cardiomyopathy[133] In the same population MCP-1 (monocyte chemo-attractant protein-1) geneCCL2-2518A allele (rs1024611) andthe CCL2-2518 AA genotype correlate with susceptibility tochronic cardiomyopathy [134] BAT1 MCP-1 and LTA maybe involved in the pathogenesis of cardiac Chagas disease

Despite the controversial results these data suggest theinvolvement of cytokines in the course of Chagas diseaseThebalance between TH1TH2T regulatory cytokines has differ-ent and opposing influences on the likelihood of infectionwith T cruzi and on the clinical course of the Chagas disease

3 Concluding Remarks

Many genetic linkages and association studies have attemptedto identify genetic variations that are involved in immuno-pathogenesis of Chagas disease However causal genetic vari-ants underlying susceptibility remain unknown due to com-plexity of parasite and host Susceptibilityresistance to Cha-gas disease involves multiple genetic variants functioningjointly each with small or moderate effects Immunologicalmechanisms protect against the disease but contribute toaggression and tissue damage Genome wide associationstudies (GWAS) and next generation sequencing (NGS) atpresent lacking in Chagas disease may help identifying novelgenetic polymorphisms with genome scale associations

The impact of pathogens on host cell functions as wellas genetic markers that were significantly associated withdisease was found on schistosomiasis [135] ascariasis [136]leprosy [137] tuberculosis [138 139] malaria [140] dengue[141] hepatitis [142 143] andHIV-1 [144ndash147] In Chagas dis-ease the 2590T allele (rs2243250) polymorphism in the pro-moter region of IL4 gene is a marker for IL4 haplotypes likelyassociated with protection against T cruzi infection [124]

The identification of the specific genes influencing Tcruzi infection and Chagas disease through genome scanstechniques could offer a particular opportunity for mappinggenes of susceptibility or resistance Further studies are neces-sary to clarify the relationship between genotype and devel-opment of disease and its clinical outcomes

The characterisation of the susceptibility genes and theirvariants has important implications not only for a betterunderstanding of disease pathogenesis but also for the con-trol and development of new therapeutic strategies for infec-tious diseases

References

[1] C Chagas ldquoNova tripanozomiaze humana Estudos sobre amorfologia e o ciclo evolutivo do Schizotrypanum cruzi n genn sp Agente etiologico Agente etiologico de uma nova entidademorbida para o homemrdquoMemorias do Instituto Oswaldo Cruzvol 1 pp 159ndash218 1909

[2] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[3] L O Andrade C R S Machado E Chiari S D J Penaand A M Macedo ldquoDifferential tissue distribution of diverseclones of Trypanosoma cruzi in infected micerdquo Molecular andBiochemical Parasitology vol 100 no 2 pp 163ndash172 1999

[4] World Health Organization (2012) Chagas disease (Americantrypanosomiasis) Fact Sheet No 340

[5] L V Kirchhoff ldquoChanging epidemiology and approaches totherapy for Chagas diseaserdquo Current Infectious Disease Reportsvol 5 no 1 pp 59ndash65 2003

[6] C Hoare ldquoThe trypanosomes of mammalsrdquo Journal of SmallAnimal Practice vol 13 pp 671ndash672 1972

[7] C J Schofield ldquoOverview evolution of the triatominaerdquo in Pro-ceedings of the 2nd International Workshop on Population Gen-etics and Control of Triatominae C J Schofield and C PonceEds INDRE Tegucigalpa Honduras 1998

[8] F Rothhammer M J Allison L Nunez V Standen and BArriaza ldquoChagas disease in pre-Columbian South AmericardquoAmerican Journal of Physical Anthropology vol 68 no 4 pp495ndash498 1985

[9] J R Coura ldquoChagas disease what is known and what isneededmdasha background articlerdquoMemorias do Instituto OswaldoCruz vol 102 no 1 pp 113ndash122 2007

[10] A C Aufderheide W Salo M Madden et al ldquoA 9000-yearrecord of Chagas diseaserdquo Proceedings of the National Academyof Sciences of USA vol 101 no 7 pp 2034ndash2039 2004

[11] Y Carlier J C PDias AO LuquettiMHonteberye F Torricoand C Truyens ldquoTrypanosomiase americaine ou maladie deChagasrdquo in Encyclopedie Medico Chirurgicale Elsevier ParisFrence 2002

[12] W B Bean ldquoThe illness of Charles DarwinrdquoTheAmerican Jour-nal of Medicine vol 65 no 4 pp 572ndash574 1978

[13] F Koberle ldquo50 Years of Chagasrsquo diseaserdquoMunchener Medizinis-che Wochenschrift vol 99 pp 1193ndash1198 1957

[14] A Moncayo and M I Ortiz Yanine ldquoAn update on Chagasdisease (humanAmerican trypanosomiasis)rdquoAnnals of TropicalMedicine and Parasitology vol 100 no 8 pp 663ndash677 2006

[15] G A Schmunis ldquoEpidemiology of Chagas disease in non-ende-mic countries the role of internationalmigrationrdquoMemorias doInstituto Oswaldo Cruz vol 102 no 1 pp 75ndash85 2007

[16] G A Schmunis and Z E Yadon ldquoChagas disease a LatinAmerican health problem becoming a world health problemrdquoActa Tropica vol 115 no 1-2 pp 14ndash21 2010

[17] J R Coura and P A Vinas ldquoChagas disease a new worldwidechallengerdquo Nature vol 465 no 7301 pp S6ndashS7 2010

[18] A F Henao-Martınez D A Schwart and I V Yang ldquoChagasiccardiomyopathy from acute to chronic is this mediated byhost susceptibility factorsrdquo Transactions of the Royal Society ofTropicalMedicine andHygiene vol 106 no 9 pp 521mdash527 2012

[19] D P Neves A L Melo and O Genaro Eds ParasitologiaHumana Atheneu Sao Paulo Brazil 2005

[20] D Born R E S Acha and M Ferraz ldquoPregnancy and Chagasrsquodiseaserdquo Journal of the American College of Cardiology vol 31p 421 1998

[21] E L P Camandaroba C M Pinheiro Lima and S G AndradeldquoOral transmission of Chagas disease importance of Trypano-soma cruzi biodeme in the intragastric experimental infectionrdquoRevista do Instituto de Medicina Tropical de Sao Paulo vol 44no 2 pp 97ndash103 2002

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Microbiology

Page 3: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

BioMed Research International 3

and molecular characterisation of the parasitersquos DNA by thepolymerase chain reaction (PCR) [28] During the acutephase the majority of infected individuals develop a humoraland cellular immune response responsible for the decrease ofparasites in the blood

After that the patients progress to the chronic asymp-tomatic stage that affects most individuals (50 to 60)this condition characterises the indeterminate clinical form(IND) of the disease and it may remain for long periodsof time [23 27] About 20 to 30 develop cardiomyopa-thy that reflects a myocardium progressively damaged byextensive chronic inflammation and fibrosis and in terminalphases usually presents as dilated cardiomyopathy ChronicChagas cardiomyopathy (CCC) is the most relevant clinicalmanifestation causing death from heart failure in endemiccountries and accounts for a significant burden of ischaemicand inflammatory heart diseases in the USA and Europe dueto ldquoglobalisationrdquo of Chagas disease Eight to 10 has thedigestive form characterised by dilation of the oesophagus orcolon (megaoesophagus andmegacolon) Some patients haveassociated cardiac and digestivemanifestations known as themixed or cardiodigestive form [17 29 30]

The transition from acute to chronic phase is accom-panied by a marked decrease in parasitaemia due to themounting of a relatively effective immune response whichkeeps parasite frequency at below detectable levels in thehost To diagnose the disease regardless of stage the sero-logical test is used by detecting antibodies specific to theparasite IgM (acute phase) and IgG (indeterminate andchronic phase) [31] Conventional serological tests includeprimarily immunofluorescence assays (IFA) enzyme-linkedimmunosorbent assays (ELISA) and indirect haemaggluti-nation assays (IHA)These tests were summarised by Afonsoet al [32] Changes in the chronic phase can be revealed byelectrocardiogram clinical diagnosis X-rays and ultrasound[27 33]

16 Host Immune Response There is a consensus that duringT cruzi infection the host immune system induces complexprocesses to ensure the control of parasite growth Theimmune response is crucial for protection against diseasehowever immunological imbalances can lead to heart anddigestive tract lesions in chagasic patients Several studieshave evaluated the innate cellular and humoral immuneresponses in chagasic patients in an attempt to correlateimmunological findings with clinical forms of Chagas dis-ease However in all clinical forms of Chagas disease theinvolvement of cell-mediated immunity is undoubtedly ofmajor importance [34ndash36]

It is also accepted that T cruzi induces a strong activationof the immune system during acute infection and that thedifferent immunological mechanisms triggered during theearly indeterminate stages of the infection may representan essential component of the immune activity observedduring ongoing clinically distinct chronic infection Afterinvasion of infectious metacyclic trypomastigotes in themammalian host T cruzi infects a variety of cell types suchas macrophages and fibroblasts Fibroblasts are numerousin the extracellular matrix of the skin and are refractory

to apoptosis [37] unlike macrophages and cardiomyocytesInfected macrophages initiate the molecular interactions thatmobilise the innate immune response of the host by sec-retion of proinflammatory cytokines like tumour necrosisfactor alpha (TNF-120572) and interleukin- (IL-) 12 [38] Thesecytokines activate Natural Killer (NK) cells to produce inter-feron-gamma (IFN-120574) that acts directly on macrophagesactivating them for antimicrobial activity Activated macro-phages produce nitric oxide (NO) via NO synthase (iNOSNOS2) potent against T cruzi Furthermore the regulatorycytokinesmdashIL-4 IL-10 and transforming growth factor beta(TGF-120573)mdashinhibit the production of NO and trypanocidalactivity of activated macrophages is responsible for disablingthe control of lethal inflammatory effects of type 1 cytokinesproduced during infection [39]

Uncontrolled activation of NK cells andmacrophages canlead to tissue damage According to Vitelli-Avelar et al [40]there is a mixed profile of cytokine production and highlevels of IFN-120574 TNF-120572 and IL-4 favour the generation ofinflammatory mechanisms This intense inflammatory pro-cess during the initial infection is essential to confine the aeti-ologic agent in the intracellular site (limiting infection andsymptoms) and prevent tissue damage but can be determin-ant to immunopathology

The lesions of the acute phase of the disease are charac-terised by the presence of localised inflammatory reactionswith a predominance of mononuclear cells at the foci ofthe pseudocyst ruptures occasionally with the formation ofgranulomas located mainly in muscle and cardiac tissue [17]

There is a robust immune response displayed in the INDdespite the complete lack of clinical disease Many studiesconcerning the cellular immune response in the IND havebeen performed Peripheral blood cells from these patientsproliferate when stimulated with antiepimastigote antibodies[35] Analysis of the expression of activation markers by T-cells showed that INDpatients have a high frequency of CD4+and CD8+ T-cells expressing HLA-DR and CD45RO [33]Moreover the vastmajority of these T-cells do not express thecostimulatory molecule CD28 [35] which suggested that thissubpopulation displayed down-modulatory activity due tointrinsic regulation via CTLA-4 In mice deficiency in eitherclass I- or class II-restricted T-cell populations was observedas a striking similarity in their mortality rate [41] Given thatCD8+ T-cells seem to be the best candidate for tissue destruc-tion it is possible that this regulatorymechanism working intandem with others helps prevent pathology in IND [42]

Despite it being considered for decades that the adaptiveimmune response is the most important protective mecha-nism during chronic infection recent studies have suggestedthe importance of the innate response as a regulatory mech-anism for controlling morbidity during disease Monocytesfrom IND patients in vitro lead to a high expression of IL-10 consistent with a modulatory response CD3-D16+CD56+

and CD3minus CD16+ CD56dim NK cells counts are particularlyhigh suggesting a protective role of this cell subpopulationCD56dim NK cells had more cytotoxic activity and can con-tribute to the control of parasitism Added to this asymp-tomatic patients exhibited Treg cells (CD4+CD25high) NKT

4 BioMed Research International

regulatory cells (CD3minusCD56+CD16+) and macrophage-likeregulatory cells (CD14+CD16+) that encourage the establish-ment and maintenance of the IND form [39 43]

CCC is associated with the presence of an intense inflam-matory infiltrate in the myocardium especially at sites whereT cruzi antigens are observed The infiltrate was composedespecially by CD8+ T-cells IL-7 and IL-15 are critical formaintenance of these cells and their activation state in theheart tissue of CCC [44] CD8+ T-cells are also found in thecirculation Similar to what was described in IND patientsCD8+ and CD4+ cells present high expression of HLA-DRand lower expression of CD28 however here CD4+ cellswere correlated with the expression of TNF-alpha [35 36] aswell as IFN-120574 The latter cytokine is higher in CCC than INDpatients andmay be a key factor in the development of severecardiomyopathy [45] Monocytes from cardiac patients alsoproduce TNF-120572 and IL-10 Although cells from CCC patientsare able to produce IL-10 the ratio of this cytokine seems tobe lower in cardiac patients [45]

During the T cruzi-cardiomyocyte interaction the par-asite has control of the host cell gene expression includingexpression of genes related to immune response inflamma-tion cytoskeletal organisation cell-cell and cell-matrix inter-actions apoptosis cell cycle and oxidative stress [46] Theintense production of cytokines chemokines and nitricoxide that are essential elements of the defensive reaction incardiac tissue can also result in cardiac hypertrophyThe acti-vation of the host cell apoptotic machinery by pathogens isan offensive strategy to eliminate the hostrsquos immune response[47]

Megaoesophagus and megacolon are the major causesof morbidity in the digestive clinical form of chronic Cha-gas disease Inflammatory infiltrates and fibrosis are foundassociated with lesions of muscle cells and of the intramuralnervous system They are composed mainly of CD3+CD4+T lymphocytes CD20+ B lymphocytes CD57+ NK cellsand CD68+ macrophage-like cells [48] Correa-Oliveira etal [45] observed that patients with the gastrointestinal formof Chagas disease demonstrated a significant decrease in theabsolute number of CD3+ T-cells as well as in CD19+ Blymphocytes and an inversion of the CD4CD8 ratio con-trastingwith results fromCCCwhere the ratio of these cells isnormal Chagasic patients with megacolon present increasednumbers of eosinophils and mononuclear cells [49] Thesecells are associatedwith inflammatory processes and can con-tribute to tissue injury through the secretion of cytokinessuch as IL-1 TNF-120572 and IL-6 which activate the cytotoxicprocess [50]

17 Pathogenesis in Chagas Disease Based on the relationshipof parasite and host interaction the mechanisms of patho-genesis in human Chagas disease can be based on two mainhypotheses The first defends the pivotal role of parasitersquospersistence in the host as a major cause of pathology whilethe other postulates that an immune response against self-antigens is responsible for the tissue damage observed inaffected organs of chagasic individuals

T cruzi exhibits multiple strategies to ensure its estab-lishment and persistence in the host Although this parasite

has the ability to infect different organs heart impairmentis the most frequent clinical manifestation of the diseaseCalvet et al [47] reviewed the current understanding ofmole-cules involved in T cruzi-cardiomyocyte recognition themechanism of invasion and the effect of intracellular devel-opment of T cruzi on the structural organisation and molec-ular response of the target cell The nature of the myocardialchanges in the chronic stage has been considered by some tobe an autoimmune phenomenon based on antigenicmimicryin the form of an antibody targeting T cruzi polypeptides[51] More recently however persistence of the parasite in thetissues has been demonstrated [52]

Although the theories are controversial autoreactivityand parasite persistence theories are not mutually exclusiveThe variation in pathologicalmanifestation has been reportedand was related to differences in host immune response suchas the ability to control parasitaemia the strength of inflam-matory reactions and the induction of autoimmune-likeresponses [53]

2 Genetic Factors and Their Influence onChagas Disease

The advance in knowledge about infection and disease haschanged the concept of infectious diseases and the geneticmarkers play an important role in this area [54] The spec-trum of expression of Chagas disease brings strong evidenceof the influence of the genetic factors on its clinical course[55]

The polymorphisms of the genes involved in the innateand specific immune response are being widely studied inorder to clarify their possible role in the occurrence or sever-ity of disease To identify possible host genetic factors thatmay influence the clinical course of Chagas disease the roleof classic and nonclassic major histocompatibility complex(MHC) genes killer cell immunoglobulin-like receptor (KIR)genes and cytokine genes that are involved in the immuneresponse will be addressed

21 Strategy for Screening and Selecting Studies This reviewabout genetic factors and their influence on Chagas diseaseselected original articles carried out on humans that werefound in the databases of PubMed (US National Library ofMedicine) LILACs (Latin American and Caribbean Centeron Information in Health Sciences) and Google ScholarTheresearch period covered included the limit of databases untilMarch 2013 There was no restriction regarding languageIn the PubMed database MeSH (Medical Subject HeadingTerms) were used and in the LILACS descriptors wereused In order to retrieve articles of interest free termswere used in the LILACS and Google Scholar The MeSHterms descriptors and free terms were organized accordingto thematic groups (i) HLA and Chagas disease (ldquoChagasDiseasegeneticsrdquo OR ldquoChagas Diseaseimmunologyrdquo ANDldquoHLAAntigensgeneticsrdquoOR ldquoHLA antigensimmunologyrdquo)(ii) MIC and Chagas disease (ldquoChagas diseasegeneticsrdquoAND ldquoMHC class I-related chain Ardquo) (iii) KIR genes andChagas disease (ldquoChagas diseasegeneticsrdquo AND ldquoReceptorsKIRgeneticsrdquo) (iv) Cytokine genes and Chagas disease

BioMed Research International 5

Potentially relevant citations at electronic databases (n = 173)

Citations which failed in the inclusion no human aimoriginality duplicate articles and double data criteria (n = 139)

Potentially relevant articles for analysis related to immuneresponse genes in association with Chagas disease (n = 34)

Articles which were added from reference list (n = 6)

40 original articles on human infections included in this review

Figure 1 Flow chart of the study for review

(ldquoChagas diseasegeneticsrdquo AND ldquocytokinesgeneticsrdquo ORldquoChemokinesgeneticsrdquo OR ldquoReceptors cytokinegeneticsrdquoThe immune response genes as HLA KIR MIC and cyto-kines and their association with Chagas disease and its clin-ical forms in the American Latin population were presentedThe results were summarized in Figure 1 and the selectedstudies are presented in Tables 1 and 2

22 HLA and Chagas Disease To identify possible host gen-etic factors that may influence the clinical course of Chagasdisease the molecules and genes in the region of the humanleucocyte antigen (HLA) have been analysed in patientspresenting with differing clinical symptoms

The highly polymorphic HLA class I (A B and C) andII (DR DQ and DP) molecules determine the efficiency ofpresentation of the T cruzi epitopes to CD8+ and CD4+ T-cells respectively The type of the presentation could affectthe clinical course of diseases because patients may responddifferently to the same antigen depending on their HLArepertory [56]

HLA alleles and haplotypes associated with Chagas dis-ease are summarized in Table 1

Several HLA alleles and haplotypes have been reportedto be associated with Chagas disease In Venezuela a studycomparing class II allele frequencies between patients andcontrols identified a decreased frequency of DRB1lowast14 andDQB1lowast0303 in patients suggesting independent protectiveeffects to chronic infection in this population In thissame study a higher frequency of DRB1lowast01 DRB1lowast08 andDQB1lowast0501 and a decreased frequency of DRB1lowast1501 werefound in patients with arrhythmia and congestive heartfailure [57] In an endemic area of central Venezuela a higherfrequency of the HLA-DPB1lowast0401 allele and DPB1lowast0401-HLA-DPB1lowast2301 or DPB1lowast0401-DPB1lowast3901 haplotype was

found in patients with cardiac manifestations [58] Sus-ceptibility between HLA-Clowast03 and CCC Venezuelan wasconfirmed [59]

In Chile HLA-B40 antigen in the presence of Cw3 wassignificantly lower in subjects with CCC [60] and was foundin higher expression in patients without evidence of heartdisease in Santiago [61]

An increase of HLA-A31 B39 and DR8 and a decreaseof HLA-DR4 DR5 DQ1 and DQ3 were observed in severalLatin American mestizos from different countries and withCCC [62]

A study in south-eastern Brazil showed that HLA-Alowast30was involved in susceptibility to Chagas disease whereasHLA-DQB1lowast06 was related to protection regardless of theclinical form of the disease [63] and HLA-DR2 was asso-ciated with susceptibility to chronic Chagas disease in asouth Brazilian population [64] However in another studythe polymorphism of HLA-DR and -DQ does not influencethe susceptibility to different clinical forms of Chagas dis-ease or the progression to severe Chagasrsquo cardiomyopathy[65]

The haplotype HLA-DRB1lowast14-DQB1lowast0301 was involvedin resistance to infection with T cruzi in a rural mestizopopulation of southern Peru [66]

In the Mexican population HLA-DR4 and HLA-B39were associated with the infection by the T Cruzi whereasHLA-DR16 was a marker of susceptibility to damage tothe heart and HLA-A68 was related with protection todevelopment of CCC [67]

In Argentina the class II allele HLA-DRB1lowast0409 andDRB1lowast1503 was significantly more prevalent in Chagas dis-ease and DRB1lowast1103 allele was associated with disease resist-ance Increased frequency of DRB1lowast1503 allele was foundamong CCC suggesting susceptibility [68 69]

In Bolivia the frequencies of HLA-DRB1lowast01 and HLA-Blowast1402 were significantly lower in patients suffering frommegacolon as well as in those with ECG alteration andormegacolon compared with a group of IND patientsThe DRB1lowast0102 Blowast1402 and MICAlowast011 alleles were instrong linkage disequilibrium and the HLA-DRB1lowast01-Blowast14-MICAlowast011 haplotype was associated with resistance againstchronic Chagas disease [70]

These different results between the HLA allele and hap-lotypes and Chagas disease could be caused by variability ofHLA allelersquos distribution in different ethnic groups the typingtest (serological or molecular techniques) the methods ofstatistical analyses (simple chi-square test and logistic orlinear regression) and interpretation (119875 value or 119875

119888value that

applies the Bonferroni correction for multiple comparisons)the selection of the patients and the clinical form the num-bers of individuals linkage disequilibrium and biologicalvariability of the parasite Nevertheless genetic factors relatedto the HLA system reflect an important role in susceptibilityor protection to Chagas disease and its clinical forms

23 MIC and Chagas Disease The HLA region containsnot only classical HLA genes but also a wide variety ofimmunologically relevant genes such as nonclassical class Igenes (MICAMICB major histocompatibility complex class

6 BioMed Research International

Table 1 Alleles and haplotypes HLA associated with Chagas disease

HLA class I alleles andhaplotypes

HLA class II alleles andhaplotypes Population Clinical forms Association Reference

aDRB1lowast01 DQB1lowast0303 Venezuela Chronic phase Protection [57]aDRB1lowast1501 CCC Protection [57]aDRB1lowast08 CCC Susceptibility [57]aDRB1lowast01 DQB1lowast0501 CCC Susceptibility [57 58]aDPB1lowast0401aDPB1lowast0401ndashlowast2301aDPB1lowast0401ndashlowast3901 haplotypes CCC Susceptibility [58]

bClowast03 CCC Susceptibility [59]aHLA-B40-Cw3 haplotype Chile CCC Protection [60 61]bHLA-Alowast30 Brazil All clinical form Susceptibility [63]

bDQB1lowast06 All clinical form Protection [63]bDR2 Chronic phase Susceptibility [64]

No association [65]bDRB1lowast14-DQB1lowast0301 haplotype Peru Infection Protection [66]

bHLA-B39 bHLA-DR4 Mexico Infection Susceptibility [67]bHLA-B35 bHLA-DR16 CCC SusceptibilitybHLA-A68 CCC Protection

bDRB1lowast0409 and lowast1503 Argentina Infection Susceptibility [68 69]bDRB1lowast1103 Infection Protection [69]bDRB1lowast1503 CCC Susceptibility [69]

bHLA-Blowast1402 bHLA-DRB1lowast01 Bolivian DG or mixed Protection [70]bHLA-DRB1lowast01-Blowast14-MICAlowast011haplotype Infection Protection [70]

bHLA-B35-MICA-A5haplotype Guatemala CCC Susceptibility [79]

bA31 and B39 bDR8 Latin American mestizos CCC Susceptibility [62]bDR4 DR5 DQ1 DQ3 CCC Protection

a119875 value le 005 or b

119875119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

I chain-related genes A and B) thatmay be involved in diseasepathogenesis

TheMICAmolecules are recognised by lymphocytes T120574120575lymphocytes T120572120573 CD8+ and NK cells via their receptorsNKG2D present on their surfaces in association with theDAP10 molecule an adapter protein membrane [71 72] Thiscomplex NKG2D-MICA activates the phosphorylation oftyrosine residues of themolecule DAP10 triggering a cascadeof cell signalling that ends with the process of cell lysis of thetarget cells [72] A study by Steinle et al [73] showed thatchanging a single amino acidmdasha methionine for a valine atposition 129 of the1205722 domain of the heavy chainmdashcategorisesthe MICA as strong (MICA-129met) and weak (MICA-129val) ligands of NKG2D affecting the activation of NK cells

MICA and MICB are weakly expressed on healthy cellsbut their expression is induced in response to cellular stressin many cell types including epithelial cells fibroblastskeratinocytes endothelial cells and monocytes [74ndash77]

The polymorphism of MICA may be involved in sus-ceptibility to various diseases but it has been suggestedthat this association may be secondary due to the strong

linkage disequilibrium with HLA-B alleles Groh et al [78]found that MICAlowast011 which was closely linked to HLA-Blowast14 and DRB1lowast01 might stimulate T120574120575 cells in the gutmucosa a phenomenon that could relate to megacolonIn Chagas disease the same HLA-DRB1lowast01-Blowast14-MICAlowast011haplotype was associated with resistance against the chronicform [70] MICA-A5 and HLA-B35 synergistically enhancedsusceptibility to CCC [79]

24 Association of KIR Genes and Their HLA Ligands withChagas Disease Other receptors of NK cells that recogniseHLA class I molecules present on the target cells includedKIR (killer cell immunoglobulin-like receptor) [80 81] KIRreceptors are glycoproteins that belong to the immunoglobu-lin superfamily and which are also found in some subpopu-lations of T-cells [82] KIR genes are clustered in the 19q134region and are characterised by both allelic (high numbersof variants) and haplotypic (different numbers of genes forinhibitory and activating receptors on individual chromo-somes) polymorphismsThe specific KIR-HLA combinationsmay regulate NK cell-mediated immunity against infectious

BioMed Research International 7

Table 2 Polymorphisms in cytokines genes and their association with Chagas disease

Geneallelegenotype Population Clinical form Association ReferenceTNFA minus308 minus244 minus236and TNFB Peru Infection and CCC No association [106]

bTNF minus308A Mexico Infection and CCC Susceptibility [108]TNF minus308A Brazil CCC No association [107]aTNF minus238A Brazil Infection Susceptibility [109]aTNF minus1031C and minus308A Colombia CCC Susceptibility [110]aTNFA minus1031TT andminus308GG Colombia CCC Protection [110]aTNFa2 TNFa7 TNFa8TNFb2 TNFb4 TNFd5TNFd7 TNFe2

Brazil CCC DG or mixed Protection [111]

aTNFb7 and TNFd3 Brazil CCC and mixed Susceptibility [111]aTNFa2 Brazil CCC Susceptibility [112]bLTA +80C and LTA +252G Brazil CCC Susceptibility [113]bLTA +80A +252Ahaplotype Brazil CCC Protection [113]

IL6 minus174GC PeruColombia Infection No association [114]bIL minus1RN4CC Mexico CCC Susceptibility [115]bIL1B +5810G allele andIL1B minus31 +395 CT genotype Colombia CCC Susceptibility [116]

aIL10 minus1082A and minus1082AA Brazil CCC Susceptibility [119]IL10 Colombia Infection No association [120]aIFNG +874A and +874AA Colombia Infection Susceptibility [122]aIL4 minus590T Bolivia Infection Protection [124]aIL4RA +148AA CCC Susceptibility [120]aTGFB110C and CC PeruColombia Infection Susceptibility [126]bIL12B 31015840 UTR C and CC Colombia CCC Susceptibility [127]aCXCL9CC and CXCL10GG Brazil CCC Protection [129]CCR5CC CCC Susceptibility [129]abCCR5 minus2554T minus2733G59029G 59029AG59029GG

PeruColombiaVenezuela CCC Susceptibility [130ndash132]

aCCL2 minus2518A and AA Brazil CCC Susceptibility [133]aBAT1 22C 348C Brazil CCC Susceptibility [134]a119875 value le 005 b119875

119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

pathogens and contribute to diverse susceptibility to diseasesand other clinical situations

Several studies have shown the participation ofKIR genesand their ligands in infectious diseases [83ndash89] autoimmuneor inflammatory diseases [90ndash92] cancer [93ndash95] and in thesuccess of transplantation [96] However there are no dataavailable on the role ofKIR genes in the immunopathogenesisof Chagas disease

25 Association of Polymorphisms in Cytokine Genes withChagas Disease Immunomodulatory cytokines secreted byT-cells and macrophages are molecules that act as mediatorsof inflammation and immune response These moleculesare key components in the pathogenesis of many diseasesincluding infectious diseases cancer metabolic disorders

autoimmunity and inflammatory conditions The cytokinesare important for parasitic control and are involved in thegenesis of lesions [97]

It is known that the production of some cytokines isunder genetic control and is influenced by polymorphisms inseveral cytokine genes SNPs ormicrosatellitesmainly locatedin regulatory regions may affect gene transcription and causeinterindividual variations Some of these polymorphismsinfluence the level of cytokine production which can conferflexibility in the immune response [98ndash101] Thus the pres-ence of certain alleles may influence the course of bacterialand viral infections [102 103] and confer susceptibility orresistance to autoimmune disease [104] SNPs in cytokinegenes have been described as important genetic factors in theoccurrence of different clinical forms of Chagas disease The

8 BioMed Research International

genetic susceptibility of single nucleotide polymorphisms incytokine genes to human Chagas disease was reviewed [105]The cytokines polymorphisms associatedwithChagas diseaseare summarized in Table 2

Proinflammatory cytokines play a key role in the develop-ment of CCC Aiming to investigate the influence of theTNF polymorphisms on Chagas disease TNFA (posi-tions minus308 rs1800629 minus244 rs673 minus238 rs361525 andminus1031 rs1799964) and TNFB genotypes have been inter-rogated No significant differences were observed withthese alleles or haplotypes between patients and controls in aPeruvian population [106]TNF-308A alsowas not associatedwith CCC in Brazilian patients [107] However the sameSNP could be directly involved in the genetic susceptibilityof the chronic phase and CCC in a Mexican population[108] Another study also in Brazilian patients suggestedthat allele TNF-238A which correlates with production ofsignificantly higher levels of TNF-120572 could influence thesusceptibility to infection [109] The TNF-1031C and -308Aalleles were significantly associated with the development ofCCC whereas the TNF-1031TT and -308GG genotypes wereassociated with lower risk to develop CCC in a Colombianpopulation [110] Regarding the TNF gene microsatellite tenalleles were associated with Chagas disease in the Brazilianpopulation eight of them correlate with susceptibility(TNFa2 TNFa7 TNFa8 TNFb2 TNFb4 TNFd5 TNFd7and TNFe2) and two with protection (TNFb7 and TNFd3)against the development of the disease [111] Previously theoccurrence of the TNFa2 microsatellite was correlated withreduced survival in severe cardiomyopathy [112] Despite thecontroversial results these data suggest the involvement ofTNF in the course of Chagas disease

Clinical genetic and epidemiological studies have linkedlymphotoxin-120572 (LTA) a proinflammatory cytokine to coro-nary artery disease and myocardial infarction In BrazilianCCC patients homozygosity with respect to the LTA+80C(rs2239704) and LTA+252G (rs909253) alleles was signifi-cantly more frequent and was associated with susceptibil-ity and the haplotype LTA+80A+252A was associated withprotection against CCC Furthermore homozygosity for theLTA+80A allele correlated with the lowest levels of plasmaticTNF-120572 [113]

It appears that IL6 gene polymorphism does not con-tribute to susceptibility in the clinical manifestations ofChagas disease In a study in two independent populationsof Colombia and Peru no difference was observed for IL6-174GC (rs1800795) between Chagas disease and controls orbetween asymptomatic patients and CCC [114]

Some IL1B alleles and haplotypes have been associatedwith susceptibility to inflammatory autoimmune and infec-tious diseases The IL1B-511(rs16944) IL1F103 (rs3811058)IL1RN4 (rs419598) IL1RN 61 (rs315952) and IL-1RN 62(rs315951) polymorphisms were analysed in Chagas diseaseand IL-1RN4CC genotype was clearly associated with Tcruzi infection and CCC development [115] The IL1B+5810G(rs1143633) allele and the haplotype IL1B-31 (rs1143627)+3954(rs1143634)CT were associatedwith an increased risk of CCC[116] Therefore these studies suggest that IL1 gene clusterpolymorphisms may play a relevant role in the susceptibility

to development of CCC and that the effect of IL1B gene onchagasic cardiomyopathy predisposition is dose dependent[116]

IL-10 and INF-120574 production by T cells promotes T cruzicontrol and protects against fatal acute myocarditis [115ndash118]The SNP IL10-1082 (rs1800896) A allele which is associatedwith a lower expression of IL-10 had higher frequency inCCC Brazilian patients when compared to the asymptomaticgroup [119]However inColombian patients no differences inallele frequency and haplotype of the IL10 genewere observedin symptomatic and asymptomatic patients [120] Linkagedisequilibrium analysis on microsatellite loci suggests epis-tasis between MHC and IL-10 on Chagas disease suscep-tibilityresistance [121] The frequency of the IFNG+874AA(rs62559044) which is associated with reduced productionof INF-120574 was increased in the Colombian patients suggestingthat this SNP may be involved in susceptibility but not in theprogression of Chagas disease [122]

IL-4 is described as a prototypical anti-inflammatorycytokine It can modulate the host and parasite survivals thatdepend on a fine balance betweenTh1 responses on one handit will control parasitism and on the other hand enhanceheart inflammation throughout the course of the infection[123] In a Bolivian population SNP IL4-590 (rs2243250)T allele was associated with protection against T cruziinfection [124] although in another study only the IL4RA(IL-4 receptor-120572 rs147781) +148AA genotype showed a weakassociation with the development of CCC [120]

TGF-120573 plays a pivotal role in Chagas disease not onlyin the development of chagasic cardiomyopathy but also inmany stages of the T cruzi life cycle and survival in the hostcell environment through regulation of (i) parasite invasionof heart cells (ii) an intracellular parasite cycle (iii) inflam-mation and immune response (iv) heart fibrosis and remod-elling and (v) gap junction modulation and heart conduc-tion [125] Several SNPs in the TGFB1 gene that may affectcytokine production have been described A significant dif-ference in the distribution of the TGFB1 10 (rs1982073) T andC alleles between patients and healthy controls was observedin the Peruvian and Colombian populations TGFB1 10CCthe high producer genotype was increased in patients of bothpopulations [126]

The IL-12 family of cytokines can influence Th17 andthe production of IL-17 and INF-120574 The SNPs rs3212227 inthe 31015840UTR of the gene IL12B were investigated and IL12B31015840UTR C allele and CC genotype were significantly increasedamong CCC patients when compared to asymptomatic indi-viduals [127]

MIF (macrophage migration inhibitory factor) minus173Callele and CC genotype were related to the major risk ofChagas disease in the Colombian and Peruvian populations[128]

Some chemokines also had been associated with thedevelopment of CCC CXCL9 CC (rs10336) and CXCL10GG (rs3921) genotypes were less frequent and CCR5 CC(rs1799988) was more frequent in patients with left ven-tricular dysfunction compared with patients without thisdysfunction and may indicate that CXCL9 and CXCL10 aremaster regulators of myocardial inflammatory cell migration

BioMed Research International 9

perhaps affecting clinical progression to the life-threateningform of CCC [129] Some SNPs of CCR5 gene were associ-ated with the development of severe cardiomyopathy in anendemic area of Colombia Peru and Venezuela [130ndash132]

In the Brazilian population BAT1 (HLA-B associatedtranscript 1) C allele and CC genotype at positions 22 CGand minus348 CT were associated with risk of cardiomyopathy[133] In the same population MCP-1 (monocyte chemo-attractant protein-1) geneCCL2-2518A allele (rs1024611) andthe CCL2-2518 AA genotype correlate with susceptibility tochronic cardiomyopathy [134] BAT1 MCP-1 and LTA maybe involved in the pathogenesis of cardiac Chagas disease

Despite the controversial results these data suggest theinvolvement of cytokines in the course of Chagas diseaseThebalance between TH1TH2T regulatory cytokines has differ-ent and opposing influences on the likelihood of infectionwith T cruzi and on the clinical course of the Chagas disease

3 Concluding Remarks

Many genetic linkages and association studies have attemptedto identify genetic variations that are involved in immuno-pathogenesis of Chagas disease However causal genetic vari-ants underlying susceptibility remain unknown due to com-plexity of parasite and host Susceptibilityresistance to Cha-gas disease involves multiple genetic variants functioningjointly each with small or moderate effects Immunologicalmechanisms protect against the disease but contribute toaggression and tissue damage Genome wide associationstudies (GWAS) and next generation sequencing (NGS) atpresent lacking in Chagas disease may help identifying novelgenetic polymorphisms with genome scale associations

The impact of pathogens on host cell functions as wellas genetic markers that were significantly associated withdisease was found on schistosomiasis [135] ascariasis [136]leprosy [137] tuberculosis [138 139] malaria [140] dengue[141] hepatitis [142 143] andHIV-1 [144ndash147] In Chagas dis-ease the 2590T allele (rs2243250) polymorphism in the pro-moter region of IL4 gene is a marker for IL4 haplotypes likelyassociated with protection against T cruzi infection [124]

The identification of the specific genes influencing Tcruzi infection and Chagas disease through genome scanstechniques could offer a particular opportunity for mappinggenes of susceptibility or resistance Further studies are neces-sary to clarify the relationship between genotype and devel-opment of disease and its clinical outcomes

The characterisation of the susceptibility genes and theirvariants has important implications not only for a betterunderstanding of disease pathogenesis but also for the con-trol and development of new therapeutic strategies for infec-tious diseases

References

[1] C Chagas ldquoNova tripanozomiaze humana Estudos sobre amorfologia e o ciclo evolutivo do Schizotrypanum cruzi n genn sp Agente etiologico Agente etiologico de uma nova entidademorbida para o homemrdquoMemorias do Instituto Oswaldo Cruzvol 1 pp 159ndash218 1909

[2] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[3] L O Andrade C R S Machado E Chiari S D J Penaand A M Macedo ldquoDifferential tissue distribution of diverseclones of Trypanosoma cruzi in infected micerdquo Molecular andBiochemical Parasitology vol 100 no 2 pp 163ndash172 1999

[4] World Health Organization (2012) Chagas disease (Americantrypanosomiasis) Fact Sheet No 340

[5] L V Kirchhoff ldquoChanging epidemiology and approaches totherapy for Chagas diseaserdquo Current Infectious Disease Reportsvol 5 no 1 pp 59ndash65 2003

[6] C Hoare ldquoThe trypanosomes of mammalsrdquo Journal of SmallAnimal Practice vol 13 pp 671ndash672 1972

[7] C J Schofield ldquoOverview evolution of the triatominaerdquo in Pro-ceedings of the 2nd International Workshop on Population Gen-etics and Control of Triatominae C J Schofield and C PonceEds INDRE Tegucigalpa Honduras 1998

[8] F Rothhammer M J Allison L Nunez V Standen and BArriaza ldquoChagas disease in pre-Columbian South AmericardquoAmerican Journal of Physical Anthropology vol 68 no 4 pp495ndash498 1985

[9] J R Coura ldquoChagas disease what is known and what isneededmdasha background articlerdquoMemorias do Instituto OswaldoCruz vol 102 no 1 pp 113ndash122 2007

[10] A C Aufderheide W Salo M Madden et al ldquoA 9000-yearrecord of Chagas diseaserdquo Proceedings of the National Academyof Sciences of USA vol 101 no 7 pp 2034ndash2039 2004

[11] Y Carlier J C PDias AO LuquettiMHonteberye F Torricoand C Truyens ldquoTrypanosomiase americaine ou maladie deChagasrdquo in Encyclopedie Medico Chirurgicale Elsevier ParisFrence 2002

[12] W B Bean ldquoThe illness of Charles DarwinrdquoTheAmerican Jour-nal of Medicine vol 65 no 4 pp 572ndash574 1978

[13] F Koberle ldquo50 Years of Chagasrsquo diseaserdquoMunchener Medizinis-che Wochenschrift vol 99 pp 1193ndash1198 1957

[14] A Moncayo and M I Ortiz Yanine ldquoAn update on Chagasdisease (humanAmerican trypanosomiasis)rdquoAnnals of TropicalMedicine and Parasitology vol 100 no 8 pp 663ndash677 2006

[15] G A Schmunis ldquoEpidemiology of Chagas disease in non-ende-mic countries the role of internationalmigrationrdquoMemorias doInstituto Oswaldo Cruz vol 102 no 1 pp 75ndash85 2007

[16] G A Schmunis and Z E Yadon ldquoChagas disease a LatinAmerican health problem becoming a world health problemrdquoActa Tropica vol 115 no 1-2 pp 14ndash21 2010

[17] J R Coura and P A Vinas ldquoChagas disease a new worldwidechallengerdquo Nature vol 465 no 7301 pp S6ndashS7 2010

[18] A F Henao-Martınez D A Schwart and I V Yang ldquoChagasiccardiomyopathy from acute to chronic is this mediated byhost susceptibility factorsrdquo Transactions of the Royal Society ofTropicalMedicine andHygiene vol 106 no 9 pp 521mdash527 2012

[19] D P Neves A L Melo and O Genaro Eds ParasitologiaHumana Atheneu Sao Paulo Brazil 2005

[20] D Born R E S Acha and M Ferraz ldquoPregnancy and Chagasrsquodiseaserdquo Journal of the American College of Cardiology vol 31p 421 1998

[21] E L P Camandaroba C M Pinheiro Lima and S G AndradeldquoOral transmission of Chagas disease importance of Trypano-soma cruzi biodeme in the intragastric experimental infectionrdquoRevista do Instituto de Medicina Tropical de Sao Paulo vol 44no 2 pp 97ndash103 2002

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

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Page 4: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

4 BioMed Research International

regulatory cells (CD3minusCD56+CD16+) and macrophage-likeregulatory cells (CD14+CD16+) that encourage the establish-ment and maintenance of the IND form [39 43]

CCC is associated with the presence of an intense inflam-matory infiltrate in the myocardium especially at sites whereT cruzi antigens are observed The infiltrate was composedespecially by CD8+ T-cells IL-7 and IL-15 are critical formaintenance of these cells and their activation state in theheart tissue of CCC [44] CD8+ T-cells are also found in thecirculation Similar to what was described in IND patientsCD8+ and CD4+ cells present high expression of HLA-DRand lower expression of CD28 however here CD4+ cellswere correlated with the expression of TNF-alpha [35 36] aswell as IFN-120574 The latter cytokine is higher in CCC than INDpatients andmay be a key factor in the development of severecardiomyopathy [45] Monocytes from cardiac patients alsoproduce TNF-120572 and IL-10 Although cells from CCC patientsare able to produce IL-10 the ratio of this cytokine seems tobe lower in cardiac patients [45]

During the T cruzi-cardiomyocyte interaction the par-asite has control of the host cell gene expression includingexpression of genes related to immune response inflamma-tion cytoskeletal organisation cell-cell and cell-matrix inter-actions apoptosis cell cycle and oxidative stress [46] Theintense production of cytokines chemokines and nitricoxide that are essential elements of the defensive reaction incardiac tissue can also result in cardiac hypertrophyThe acti-vation of the host cell apoptotic machinery by pathogens isan offensive strategy to eliminate the hostrsquos immune response[47]

Megaoesophagus and megacolon are the major causesof morbidity in the digestive clinical form of chronic Cha-gas disease Inflammatory infiltrates and fibrosis are foundassociated with lesions of muscle cells and of the intramuralnervous system They are composed mainly of CD3+CD4+T lymphocytes CD20+ B lymphocytes CD57+ NK cellsand CD68+ macrophage-like cells [48] Correa-Oliveira etal [45] observed that patients with the gastrointestinal formof Chagas disease demonstrated a significant decrease in theabsolute number of CD3+ T-cells as well as in CD19+ Blymphocytes and an inversion of the CD4CD8 ratio con-trastingwith results fromCCCwhere the ratio of these cells isnormal Chagasic patients with megacolon present increasednumbers of eosinophils and mononuclear cells [49] Thesecells are associatedwith inflammatory processes and can con-tribute to tissue injury through the secretion of cytokinessuch as IL-1 TNF-120572 and IL-6 which activate the cytotoxicprocess [50]

17 Pathogenesis in Chagas Disease Based on the relationshipof parasite and host interaction the mechanisms of patho-genesis in human Chagas disease can be based on two mainhypotheses The first defends the pivotal role of parasitersquospersistence in the host as a major cause of pathology whilethe other postulates that an immune response against self-antigens is responsible for the tissue damage observed inaffected organs of chagasic individuals

T cruzi exhibits multiple strategies to ensure its estab-lishment and persistence in the host Although this parasite

has the ability to infect different organs heart impairmentis the most frequent clinical manifestation of the diseaseCalvet et al [47] reviewed the current understanding ofmole-cules involved in T cruzi-cardiomyocyte recognition themechanism of invasion and the effect of intracellular devel-opment of T cruzi on the structural organisation and molec-ular response of the target cell The nature of the myocardialchanges in the chronic stage has been considered by some tobe an autoimmune phenomenon based on antigenicmimicryin the form of an antibody targeting T cruzi polypeptides[51] More recently however persistence of the parasite in thetissues has been demonstrated [52]

Although the theories are controversial autoreactivityand parasite persistence theories are not mutually exclusiveThe variation in pathologicalmanifestation has been reportedand was related to differences in host immune response suchas the ability to control parasitaemia the strength of inflam-matory reactions and the induction of autoimmune-likeresponses [53]

2 Genetic Factors and Their Influence onChagas Disease

The advance in knowledge about infection and disease haschanged the concept of infectious diseases and the geneticmarkers play an important role in this area [54] The spec-trum of expression of Chagas disease brings strong evidenceof the influence of the genetic factors on its clinical course[55]

The polymorphisms of the genes involved in the innateand specific immune response are being widely studied inorder to clarify their possible role in the occurrence or sever-ity of disease To identify possible host genetic factors thatmay influence the clinical course of Chagas disease the roleof classic and nonclassic major histocompatibility complex(MHC) genes killer cell immunoglobulin-like receptor (KIR)genes and cytokine genes that are involved in the immuneresponse will be addressed

21 Strategy for Screening and Selecting Studies This reviewabout genetic factors and their influence on Chagas diseaseselected original articles carried out on humans that werefound in the databases of PubMed (US National Library ofMedicine) LILACs (Latin American and Caribbean Centeron Information in Health Sciences) and Google ScholarTheresearch period covered included the limit of databases untilMarch 2013 There was no restriction regarding languageIn the PubMed database MeSH (Medical Subject HeadingTerms) were used and in the LILACS descriptors wereused In order to retrieve articles of interest free termswere used in the LILACS and Google Scholar The MeSHterms descriptors and free terms were organized accordingto thematic groups (i) HLA and Chagas disease (ldquoChagasDiseasegeneticsrdquo OR ldquoChagas Diseaseimmunologyrdquo ANDldquoHLAAntigensgeneticsrdquoOR ldquoHLA antigensimmunologyrdquo)(ii) MIC and Chagas disease (ldquoChagas diseasegeneticsrdquoAND ldquoMHC class I-related chain Ardquo) (iii) KIR genes andChagas disease (ldquoChagas diseasegeneticsrdquo AND ldquoReceptorsKIRgeneticsrdquo) (iv) Cytokine genes and Chagas disease

BioMed Research International 5

Potentially relevant citations at electronic databases (n = 173)

Citations which failed in the inclusion no human aimoriginality duplicate articles and double data criteria (n = 139)

Potentially relevant articles for analysis related to immuneresponse genes in association with Chagas disease (n = 34)

Articles which were added from reference list (n = 6)

40 original articles on human infections included in this review

Figure 1 Flow chart of the study for review

(ldquoChagas diseasegeneticsrdquo AND ldquocytokinesgeneticsrdquo ORldquoChemokinesgeneticsrdquo OR ldquoReceptors cytokinegeneticsrdquoThe immune response genes as HLA KIR MIC and cyto-kines and their association with Chagas disease and its clin-ical forms in the American Latin population were presentedThe results were summarized in Figure 1 and the selectedstudies are presented in Tables 1 and 2

22 HLA and Chagas Disease To identify possible host gen-etic factors that may influence the clinical course of Chagasdisease the molecules and genes in the region of the humanleucocyte antigen (HLA) have been analysed in patientspresenting with differing clinical symptoms

The highly polymorphic HLA class I (A B and C) andII (DR DQ and DP) molecules determine the efficiency ofpresentation of the T cruzi epitopes to CD8+ and CD4+ T-cells respectively The type of the presentation could affectthe clinical course of diseases because patients may responddifferently to the same antigen depending on their HLArepertory [56]

HLA alleles and haplotypes associated with Chagas dis-ease are summarized in Table 1

Several HLA alleles and haplotypes have been reportedto be associated with Chagas disease In Venezuela a studycomparing class II allele frequencies between patients andcontrols identified a decreased frequency of DRB1lowast14 andDQB1lowast0303 in patients suggesting independent protectiveeffects to chronic infection in this population In thissame study a higher frequency of DRB1lowast01 DRB1lowast08 andDQB1lowast0501 and a decreased frequency of DRB1lowast1501 werefound in patients with arrhythmia and congestive heartfailure [57] In an endemic area of central Venezuela a higherfrequency of the HLA-DPB1lowast0401 allele and DPB1lowast0401-HLA-DPB1lowast2301 or DPB1lowast0401-DPB1lowast3901 haplotype was

found in patients with cardiac manifestations [58] Sus-ceptibility between HLA-Clowast03 and CCC Venezuelan wasconfirmed [59]

In Chile HLA-B40 antigen in the presence of Cw3 wassignificantly lower in subjects with CCC [60] and was foundin higher expression in patients without evidence of heartdisease in Santiago [61]

An increase of HLA-A31 B39 and DR8 and a decreaseof HLA-DR4 DR5 DQ1 and DQ3 were observed in severalLatin American mestizos from different countries and withCCC [62]

A study in south-eastern Brazil showed that HLA-Alowast30was involved in susceptibility to Chagas disease whereasHLA-DQB1lowast06 was related to protection regardless of theclinical form of the disease [63] and HLA-DR2 was asso-ciated with susceptibility to chronic Chagas disease in asouth Brazilian population [64] However in another studythe polymorphism of HLA-DR and -DQ does not influencethe susceptibility to different clinical forms of Chagas dis-ease or the progression to severe Chagasrsquo cardiomyopathy[65]

The haplotype HLA-DRB1lowast14-DQB1lowast0301 was involvedin resistance to infection with T cruzi in a rural mestizopopulation of southern Peru [66]

In the Mexican population HLA-DR4 and HLA-B39were associated with the infection by the T Cruzi whereasHLA-DR16 was a marker of susceptibility to damage tothe heart and HLA-A68 was related with protection todevelopment of CCC [67]

In Argentina the class II allele HLA-DRB1lowast0409 andDRB1lowast1503 was significantly more prevalent in Chagas dis-ease and DRB1lowast1103 allele was associated with disease resist-ance Increased frequency of DRB1lowast1503 allele was foundamong CCC suggesting susceptibility [68 69]

In Bolivia the frequencies of HLA-DRB1lowast01 and HLA-Blowast1402 were significantly lower in patients suffering frommegacolon as well as in those with ECG alteration andormegacolon compared with a group of IND patientsThe DRB1lowast0102 Blowast1402 and MICAlowast011 alleles were instrong linkage disequilibrium and the HLA-DRB1lowast01-Blowast14-MICAlowast011 haplotype was associated with resistance againstchronic Chagas disease [70]

These different results between the HLA allele and hap-lotypes and Chagas disease could be caused by variability ofHLA allelersquos distribution in different ethnic groups the typingtest (serological or molecular techniques) the methods ofstatistical analyses (simple chi-square test and logistic orlinear regression) and interpretation (119875 value or 119875

119888value that

applies the Bonferroni correction for multiple comparisons)the selection of the patients and the clinical form the num-bers of individuals linkage disequilibrium and biologicalvariability of the parasite Nevertheless genetic factors relatedto the HLA system reflect an important role in susceptibilityor protection to Chagas disease and its clinical forms

23 MIC and Chagas Disease The HLA region containsnot only classical HLA genes but also a wide variety ofimmunologically relevant genes such as nonclassical class Igenes (MICAMICB major histocompatibility complex class

6 BioMed Research International

Table 1 Alleles and haplotypes HLA associated with Chagas disease

HLA class I alleles andhaplotypes

HLA class II alleles andhaplotypes Population Clinical forms Association Reference

aDRB1lowast01 DQB1lowast0303 Venezuela Chronic phase Protection [57]aDRB1lowast1501 CCC Protection [57]aDRB1lowast08 CCC Susceptibility [57]aDRB1lowast01 DQB1lowast0501 CCC Susceptibility [57 58]aDPB1lowast0401aDPB1lowast0401ndashlowast2301aDPB1lowast0401ndashlowast3901 haplotypes CCC Susceptibility [58]

bClowast03 CCC Susceptibility [59]aHLA-B40-Cw3 haplotype Chile CCC Protection [60 61]bHLA-Alowast30 Brazil All clinical form Susceptibility [63]

bDQB1lowast06 All clinical form Protection [63]bDR2 Chronic phase Susceptibility [64]

No association [65]bDRB1lowast14-DQB1lowast0301 haplotype Peru Infection Protection [66]

bHLA-B39 bHLA-DR4 Mexico Infection Susceptibility [67]bHLA-B35 bHLA-DR16 CCC SusceptibilitybHLA-A68 CCC Protection

bDRB1lowast0409 and lowast1503 Argentina Infection Susceptibility [68 69]bDRB1lowast1103 Infection Protection [69]bDRB1lowast1503 CCC Susceptibility [69]

bHLA-Blowast1402 bHLA-DRB1lowast01 Bolivian DG or mixed Protection [70]bHLA-DRB1lowast01-Blowast14-MICAlowast011haplotype Infection Protection [70]

bHLA-B35-MICA-A5haplotype Guatemala CCC Susceptibility [79]

bA31 and B39 bDR8 Latin American mestizos CCC Susceptibility [62]bDR4 DR5 DQ1 DQ3 CCC Protection

a119875 value le 005 or b

119875119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

I chain-related genes A and B) thatmay be involved in diseasepathogenesis

TheMICAmolecules are recognised by lymphocytes T120574120575lymphocytes T120572120573 CD8+ and NK cells via their receptorsNKG2D present on their surfaces in association with theDAP10 molecule an adapter protein membrane [71 72] Thiscomplex NKG2D-MICA activates the phosphorylation oftyrosine residues of themolecule DAP10 triggering a cascadeof cell signalling that ends with the process of cell lysis of thetarget cells [72] A study by Steinle et al [73] showed thatchanging a single amino acidmdasha methionine for a valine atposition 129 of the1205722 domain of the heavy chainmdashcategorisesthe MICA as strong (MICA-129met) and weak (MICA-129val) ligands of NKG2D affecting the activation of NK cells

MICA and MICB are weakly expressed on healthy cellsbut their expression is induced in response to cellular stressin many cell types including epithelial cells fibroblastskeratinocytes endothelial cells and monocytes [74ndash77]

The polymorphism of MICA may be involved in sus-ceptibility to various diseases but it has been suggestedthat this association may be secondary due to the strong

linkage disequilibrium with HLA-B alleles Groh et al [78]found that MICAlowast011 which was closely linked to HLA-Blowast14 and DRB1lowast01 might stimulate T120574120575 cells in the gutmucosa a phenomenon that could relate to megacolonIn Chagas disease the same HLA-DRB1lowast01-Blowast14-MICAlowast011haplotype was associated with resistance against the chronicform [70] MICA-A5 and HLA-B35 synergistically enhancedsusceptibility to CCC [79]

24 Association of KIR Genes and Their HLA Ligands withChagas Disease Other receptors of NK cells that recogniseHLA class I molecules present on the target cells includedKIR (killer cell immunoglobulin-like receptor) [80 81] KIRreceptors are glycoproteins that belong to the immunoglobu-lin superfamily and which are also found in some subpopu-lations of T-cells [82] KIR genes are clustered in the 19q134region and are characterised by both allelic (high numbersof variants) and haplotypic (different numbers of genes forinhibitory and activating receptors on individual chromo-somes) polymorphismsThe specific KIR-HLA combinationsmay regulate NK cell-mediated immunity against infectious

BioMed Research International 7

Table 2 Polymorphisms in cytokines genes and their association with Chagas disease

Geneallelegenotype Population Clinical form Association ReferenceTNFA minus308 minus244 minus236and TNFB Peru Infection and CCC No association [106]

bTNF minus308A Mexico Infection and CCC Susceptibility [108]TNF minus308A Brazil CCC No association [107]aTNF minus238A Brazil Infection Susceptibility [109]aTNF minus1031C and minus308A Colombia CCC Susceptibility [110]aTNFA minus1031TT andminus308GG Colombia CCC Protection [110]aTNFa2 TNFa7 TNFa8TNFb2 TNFb4 TNFd5TNFd7 TNFe2

Brazil CCC DG or mixed Protection [111]

aTNFb7 and TNFd3 Brazil CCC and mixed Susceptibility [111]aTNFa2 Brazil CCC Susceptibility [112]bLTA +80C and LTA +252G Brazil CCC Susceptibility [113]bLTA +80A +252Ahaplotype Brazil CCC Protection [113]

IL6 minus174GC PeruColombia Infection No association [114]bIL minus1RN4CC Mexico CCC Susceptibility [115]bIL1B +5810G allele andIL1B minus31 +395 CT genotype Colombia CCC Susceptibility [116]

aIL10 minus1082A and minus1082AA Brazil CCC Susceptibility [119]IL10 Colombia Infection No association [120]aIFNG +874A and +874AA Colombia Infection Susceptibility [122]aIL4 minus590T Bolivia Infection Protection [124]aIL4RA +148AA CCC Susceptibility [120]aTGFB110C and CC PeruColombia Infection Susceptibility [126]bIL12B 31015840 UTR C and CC Colombia CCC Susceptibility [127]aCXCL9CC and CXCL10GG Brazil CCC Protection [129]CCR5CC CCC Susceptibility [129]abCCR5 minus2554T minus2733G59029G 59029AG59029GG

PeruColombiaVenezuela CCC Susceptibility [130ndash132]

aCCL2 minus2518A and AA Brazil CCC Susceptibility [133]aBAT1 22C 348C Brazil CCC Susceptibility [134]a119875 value le 005 b119875

119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

pathogens and contribute to diverse susceptibility to diseasesand other clinical situations

Several studies have shown the participation ofKIR genesand their ligands in infectious diseases [83ndash89] autoimmuneor inflammatory diseases [90ndash92] cancer [93ndash95] and in thesuccess of transplantation [96] However there are no dataavailable on the role ofKIR genes in the immunopathogenesisof Chagas disease

25 Association of Polymorphisms in Cytokine Genes withChagas Disease Immunomodulatory cytokines secreted byT-cells and macrophages are molecules that act as mediatorsof inflammation and immune response These moleculesare key components in the pathogenesis of many diseasesincluding infectious diseases cancer metabolic disorders

autoimmunity and inflammatory conditions The cytokinesare important for parasitic control and are involved in thegenesis of lesions [97]

It is known that the production of some cytokines isunder genetic control and is influenced by polymorphisms inseveral cytokine genes SNPs ormicrosatellitesmainly locatedin regulatory regions may affect gene transcription and causeinterindividual variations Some of these polymorphismsinfluence the level of cytokine production which can conferflexibility in the immune response [98ndash101] Thus the pres-ence of certain alleles may influence the course of bacterialand viral infections [102 103] and confer susceptibility orresistance to autoimmune disease [104] SNPs in cytokinegenes have been described as important genetic factors in theoccurrence of different clinical forms of Chagas disease The

8 BioMed Research International

genetic susceptibility of single nucleotide polymorphisms incytokine genes to human Chagas disease was reviewed [105]The cytokines polymorphisms associatedwithChagas diseaseare summarized in Table 2

Proinflammatory cytokines play a key role in the develop-ment of CCC Aiming to investigate the influence of theTNF polymorphisms on Chagas disease TNFA (posi-tions minus308 rs1800629 minus244 rs673 minus238 rs361525 andminus1031 rs1799964) and TNFB genotypes have been inter-rogated No significant differences were observed withthese alleles or haplotypes between patients and controls in aPeruvian population [106]TNF-308A alsowas not associatedwith CCC in Brazilian patients [107] However the sameSNP could be directly involved in the genetic susceptibilityof the chronic phase and CCC in a Mexican population[108] Another study also in Brazilian patients suggestedthat allele TNF-238A which correlates with production ofsignificantly higher levels of TNF-120572 could influence thesusceptibility to infection [109] The TNF-1031C and -308Aalleles were significantly associated with the development ofCCC whereas the TNF-1031TT and -308GG genotypes wereassociated with lower risk to develop CCC in a Colombianpopulation [110] Regarding the TNF gene microsatellite tenalleles were associated with Chagas disease in the Brazilianpopulation eight of them correlate with susceptibility(TNFa2 TNFa7 TNFa8 TNFb2 TNFb4 TNFd5 TNFd7and TNFe2) and two with protection (TNFb7 and TNFd3)against the development of the disease [111] Previously theoccurrence of the TNFa2 microsatellite was correlated withreduced survival in severe cardiomyopathy [112] Despite thecontroversial results these data suggest the involvement ofTNF in the course of Chagas disease

Clinical genetic and epidemiological studies have linkedlymphotoxin-120572 (LTA) a proinflammatory cytokine to coro-nary artery disease and myocardial infarction In BrazilianCCC patients homozygosity with respect to the LTA+80C(rs2239704) and LTA+252G (rs909253) alleles was signifi-cantly more frequent and was associated with susceptibil-ity and the haplotype LTA+80A+252A was associated withprotection against CCC Furthermore homozygosity for theLTA+80A allele correlated with the lowest levels of plasmaticTNF-120572 [113]

It appears that IL6 gene polymorphism does not con-tribute to susceptibility in the clinical manifestations ofChagas disease In a study in two independent populationsof Colombia and Peru no difference was observed for IL6-174GC (rs1800795) between Chagas disease and controls orbetween asymptomatic patients and CCC [114]

Some IL1B alleles and haplotypes have been associatedwith susceptibility to inflammatory autoimmune and infec-tious diseases The IL1B-511(rs16944) IL1F103 (rs3811058)IL1RN4 (rs419598) IL1RN 61 (rs315952) and IL-1RN 62(rs315951) polymorphisms were analysed in Chagas diseaseand IL-1RN4CC genotype was clearly associated with Tcruzi infection and CCC development [115] The IL1B+5810G(rs1143633) allele and the haplotype IL1B-31 (rs1143627)+3954(rs1143634)CT were associatedwith an increased risk of CCC[116] Therefore these studies suggest that IL1 gene clusterpolymorphisms may play a relevant role in the susceptibility

to development of CCC and that the effect of IL1B gene onchagasic cardiomyopathy predisposition is dose dependent[116]

IL-10 and INF-120574 production by T cells promotes T cruzicontrol and protects against fatal acute myocarditis [115ndash118]The SNP IL10-1082 (rs1800896) A allele which is associatedwith a lower expression of IL-10 had higher frequency inCCC Brazilian patients when compared to the asymptomaticgroup [119]However inColombian patients no differences inallele frequency and haplotype of the IL10 genewere observedin symptomatic and asymptomatic patients [120] Linkagedisequilibrium analysis on microsatellite loci suggests epis-tasis between MHC and IL-10 on Chagas disease suscep-tibilityresistance [121] The frequency of the IFNG+874AA(rs62559044) which is associated with reduced productionof INF-120574 was increased in the Colombian patients suggestingthat this SNP may be involved in susceptibility but not in theprogression of Chagas disease [122]

IL-4 is described as a prototypical anti-inflammatorycytokine It can modulate the host and parasite survivals thatdepend on a fine balance betweenTh1 responses on one handit will control parasitism and on the other hand enhanceheart inflammation throughout the course of the infection[123] In a Bolivian population SNP IL4-590 (rs2243250)T allele was associated with protection against T cruziinfection [124] although in another study only the IL4RA(IL-4 receptor-120572 rs147781) +148AA genotype showed a weakassociation with the development of CCC [120]

TGF-120573 plays a pivotal role in Chagas disease not onlyin the development of chagasic cardiomyopathy but also inmany stages of the T cruzi life cycle and survival in the hostcell environment through regulation of (i) parasite invasionof heart cells (ii) an intracellular parasite cycle (iii) inflam-mation and immune response (iv) heart fibrosis and remod-elling and (v) gap junction modulation and heart conduc-tion [125] Several SNPs in the TGFB1 gene that may affectcytokine production have been described A significant dif-ference in the distribution of the TGFB1 10 (rs1982073) T andC alleles between patients and healthy controls was observedin the Peruvian and Colombian populations TGFB1 10CCthe high producer genotype was increased in patients of bothpopulations [126]

The IL-12 family of cytokines can influence Th17 andthe production of IL-17 and INF-120574 The SNPs rs3212227 inthe 31015840UTR of the gene IL12B were investigated and IL12B31015840UTR C allele and CC genotype were significantly increasedamong CCC patients when compared to asymptomatic indi-viduals [127]

MIF (macrophage migration inhibitory factor) minus173Callele and CC genotype were related to the major risk ofChagas disease in the Colombian and Peruvian populations[128]

Some chemokines also had been associated with thedevelopment of CCC CXCL9 CC (rs10336) and CXCL10GG (rs3921) genotypes were less frequent and CCR5 CC(rs1799988) was more frequent in patients with left ven-tricular dysfunction compared with patients without thisdysfunction and may indicate that CXCL9 and CXCL10 aremaster regulators of myocardial inflammatory cell migration

BioMed Research International 9

perhaps affecting clinical progression to the life-threateningform of CCC [129] Some SNPs of CCR5 gene were associ-ated with the development of severe cardiomyopathy in anendemic area of Colombia Peru and Venezuela [130ndash132]

In the Brazilian population BAT1 (HLA-B associatedtranscript 1) C allele and CC genotype at positions 22 CGand minus348 CT were associated with risk of cardiomyopathy[133] In the same population MCP-1 (monocyte chemo-attractant protein-1) geneCCL2-2518A allele (rs1024611) andthe CCL2-2518 AA genotype correlate with susceptibility tochronic cardiomyopathy [134] BAT1 MCP-1 and LTA maybe involved in the pathogenesis of cardiac Chagas disease

Despite the controversial results these data suggest theinvolvement of cytokines in the course of Chagas diseaseThebalance between TH1TH2T regulatory cytokines has differ-ent and opposing influences on the likelihood of infectionwith T cruzi and on the clinical course of the Chagas disease

3 Concluding Remarks

Many genetic linkages and association studies have attemptedto identify genetic variations that are involved in immuno-pathogenesis of Chagas disease However causal genetic vari-ants underlying susceptibility remain unknown due to com-plexity of parasite and host Susceptibilityresistance to Cha-gas disease involves multiple genetic variants functioningjointly each with small or moderate effects Immunologicalmechanisms protect against the disease but contribute toaggression and tissue damage Genome wide associationstudies (GWAS) and next generation sequencing (NGS) atpresent lacking in Chagas disease may help identifying novelgenetic polymorphisms with genome scale associations

The impact of pathogens on host cell functions as wellas genetic markers that were significantly associated withdisease was found on schistosomiasis [135] ascariasis [136]leprosy [137] tuberculosis [138 139] malaria [140] dengue[141] hepatitis [142 143] andHIV-1 [144ndash147] In Chagas dis-ease the 2590T allele (rs2243250) polymorphism in the pro-moter region of IL4 gene is a marker for IL4 haplotypes likelyassociated with protection against T cruzi infection [124]

The identification of the specific genes influencing Tcruzi infection and Chagas disease through genome scanstechniques could offer a particular opportunity for mappinggenes of susceptibility or resistance Further studies are neces-sary to clarify the relationship between genotype and devel-opment of disease and its clinical outcomes

The characterisation of the susceptibility genes and theirvariants has important implications not only for a betterunderstanding of disease pathogenesis but also for the con-trol and development of new therapeutic strategies for infec-tious diseases

References

[1] C Chagas ldquoNova tripanozomiaze humana Estudos sobre amorfologia e o ciclo evolutivo do Schizotrypanum cruzi n genn sp Agente etiologico Agente etiologico de uma nova entidademorbida para o homemrdquoMemorias do Instituto Oswaldo Cruzvol 1 pp 159ndash218 1909

[2] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[3] L O Andrade C R S Machado E Chiari S D J Penaand A M Macedo ldquoDifferential tissue distribution of diverseclones of Trypanosoma cruzi in infected micerdquo Molecular andBiochemical Parasitology vol 100 no 2 pp 163ndash172 1999

[4] World Health Organization (2012) Chagas disease (Americantrypanosomiasis) Fact Sheet No 340

[5] L V Kirchhoff ldquoChanging epidemiology and approaches totherapy for Chagas diseaserdquo Current Infectious Disease Reportsvol 5 no 1 pp 59ndash65 2003

[6] C Hoare ldquoThe trypanosomes of mammalsrdquo Journal of SmallAnimal Practice vol 13 pp 671ndash672 1972

[7] C J Schofield ldquoOverview evolution of the triatominaerdquo in Pro-ceedings of the 2nd International Workshop on Population Gen-etics and Control of Triatominae C J Schofield and C PonceEds INDRE Tegucigalpa Honduras 1998

[8] F Rothhammer M J Allison L Nunez V Standen and BArriaza ldquoChagas disease in pre-Columbian South AmericardquoAmerican Journal of Physical Anthropology vol 68 no 4 pp495ndash498 1985

[9] J R Coura ldquoChagas disease what is known and what isneededmdasha background articlerdquoMemorias do Instituto OswaldoCruz vol 102 no 1 pp 113ndash122 2007

[10] A C Aufderheide W Salo M Madden et al ldquoA 9000-yearrecord of Chagas diseaserdquo Proceedings of the National Academyof Sciences of USA vol 101 no 7 pp 2034ndash2039 2004

[11] Y Carlier J C PDias AO LuquettiMHonteberye F Torricoand C Truyens ldquoTrypanosomiase americaine ou maladie deChagasrdquo in Encyclopedie Medico Chirurgicale Elsevier ParisFrence 2002

[12] W B Bean ldquoThe illness of Charles DarwinrdquoTheAmerican Jour-nal of Medicine vol 65 no 4 pp 572ndash574 1978

[13] F Koberle ldquo50 Years of Chagasrsquo diseaserdquoMunchener Medizinis-che Wochenschrift vol 99 pp 1193ndash1198 1957

[14] A Moncayo and M I Ortiz Yanine ldquoAn update on Chagasdisease (humanAmerican trypanosomiasis)rdquoAnnals of TropicalMedicine and Parasitology vol 100 no 8 pp 663ndash677 2006

[15] G A Schmunis ldquoEpidemiology of Chagas disease in non-ende-mic countries the role of internationalmigrationrdquoMemorias doInstituto Oswaldo Cruz vol 102 no 1 pp 75ndash85 2007

[16] G A Schmunis and Z E Yadon ldquoChagas disease a LatinAmerican health problem becoming a world health problemrdquoActa Tropica vol 115 no 1-2 pp 14ndash21 2010

[17] J R Coura and P A Vinas ldquoChagas disease a new worldwidechallengerdquo Nature vol 465 no 7301 pp S6ndashS7 2010

[18] A F Henao-Martınez D A Schwart and I V Yang ldquoChagasiccardiomyopathy from acute to chronic is this mediated byhost susceptibility factorsrdquo Transactions of the Royal Society ofTropicalMedicine andHygiene vol 106 no 9 pp 521mdash527 2012

[19] D P Neves A L Melo and O Genaro Eds ParasitologiaHumana Atheneu Sao Paulo Brazil 2005

[20] D Born R E S Acha and M Ferraz ldquoPregnancy and Chagasrsquodiseaserdquo Journal of the American College of Cardiology vol 31p 421 1998

[21] E L P Camandaroba C M Pinheiro Lima and S G AndradeldquoOral transmission of Chagas disease importance of Trypano-soma cruzi biodeme in the intragastric experimental infectionrdquoRevista do Instituto de Medicina Tropical de Sao Paulo vol 44no 2 pp 97ndash103 2002

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

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Page 5: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

BioMed Research International 5

Potentially relevant citations at electronic databases (n = 173)

Citations which failed in the inclusion no human aimoriginality duplicate articles and double data criteria (n = 139)

Potentially relevant articles for analysis related to immuneresponse genes in association with Chagas disease (n = 34)

Articles which were added from reference list (n = 6)

40 original articles on human infections included in this review

Figure 1 Flow chart of the study for review

(ldquoChagas diseasegeneticsrdquo AND ldquocytokinesgeneticsrdquo ORldquoChemokinesgeneticsrdquo OR ldquoReceptors cytokinegeneticsrdquoThe immune response genes as HLA KIR MIC and cyto-kines and their association with Chagas disease and its clin-ical forms in the American Latin population were presentedThe results were summarized in Figure 1 and the selectedstudies are presented in Tables 1 and 2

22 HLA and Chagas Disease To identify possible host gen-etic factors that may influence the clinical course of Chagasdisease the molecules and genes in the region of the humanleucocyte antigen (HLA) have been analysed in patientspresenting with differing clinical symptoms

The highly polymorphic HLA class I (A B and C) andII (DR DQ and DP) molecules determine the efficiency ofpresentation of the T cruzi epitopes to CD8+ and CD4+ T-cells respectively The type of the presentation could affectthe clinical course of diseases because patients may responddifferently to the same antigen depending on their HLArepertory [56]

HLA alleles and haplotypes associated with Chagas dis-ease are summarized in Table 1

Several HLA alleles and haplotypes have been reportedto be associated with Chagas disease In Venezuela a studycomparing class II allele frequencies between patients andcontrols identified a decreased frequency of DRB1lowast14 andDQB1lowast0303 in patients suggesting independent protectiveeffects to chronic infection in this population In thissame study a higher frequency of DRB1lowast01 DRB1lowast08 andDQB1lowast0501 and a decreased frequency of DRB1lowast1501 werefound in patients with arrhythmia and congestive heartfailure [57] In an endemic area of central Venezuela a higherfrequency of the HLA-DPB1lowast0401 allele and DPB1lowast0401-HLA-DPB1lowast2301 or DPB1lowast0401-DPB1lowast3901 haplotype was

found in patients with cardiac manifestations [58] Sus-ceptibility between HLA-Clowast03 and CCC Venezuelan wasconfirmed [59]

In Chile HLA-B40 antigen in the presence of Cw3 wassignificantly lower in subjects with CCC [60] and was foundin higher expression in patients without evidence of heartdisease in Santiago [61]

An increase of HLA-A31 B39 and DR8 and a decreaseof HLA-DR4 DR5 DQ1 and DQ3 were observed in severalLatin American mestizos from different countries and withCCC [62]

A study in south-eastern Brazil showed that HLA-Alowast30was involved in susceptibility to Chagas disease whereasHLA-DQB1lowast06 was related to protection regardless of theclinical form of the disease [63] and HLA-DR2 was asso-ciated with susceptibility to chronic Chagas disease in asouth Brazilian population [64] However in another studythe polymorphism of HLA-DR and -DQ does not influencethe susceptibility to different clinical forms of Chagas dis-ease or the progression to severe Chagasrsquo cardiomyopathy[65]

The haplotype HLA-DRB1lowast14-DQB1lowast0301 was involvedin resistance to infection with T cruzi in a rural mestizopopulation of southern Peru [66]

In the Mexican population HLA-DR4 and HLA-B39were associated with the infection by the T Cruzi whereasHLA-DR16 was a marker of susceptibility to damage tothe heart and HLA-A68 was related with protection todevelopment of CCC [67]

In Argentina the class II allele HLA-DRB1lowast0409 andDRB1lowast1503 was significantly more prevalent in Chagas dis-ease and DRB1lowast1103 allele was associated with disease resist-ance Increased frequency of DRB1lowast1503 allele was foundamong CCC suggesting susceptibility [68 69]

In Bolivia the frequencies of HLA-DRB1lowast01 and HLA-Blowast1402 were significantly lower in patients suffering frommegacolon as well as in those with ECG alteration andormegacolon compared with a group of IND patientsThe DRB1lowast0102 Blowast1402 and MICAlowast011 alleles were instrong linkage disequilibrium and the HLA-DRB1lowast01-Blowast14-MICAlowast011 haplotype was associated with resistance againstchronic Chagas disease [70]

These different results between the HLA allele and hap-lotypes and Chagas disease could be caused by variability ofHLA allelersquos distribution in different ethnic groups the typingtest (serological or molecular techniques) the methods ofstatistical analyses (simple chi-square test and logistic orlinear regression) and interpretation (119875 value or 119875

119888value that

applies the Bonferroni correction for multiple comparisons)the selection of the patients and the clinical form the num-bers of individuals linkage disequilibrium and biologicalvariability of the parasite Nevertheless genetic factors relatedto the HLA system reflect an important role in susceptibilityor protection to Chagas disease and its clinical forms

23 MIC and Chagas Disease The HLA region containsnot only classical HLA genes but also a wide variety ofimmunologically relevant genes such as nonclassical class Igenes (MICAMICB major histocompatibility complex class

6 BioMed Research International

Table 1 Alleles and haplotypes HLA associated with Chagas disease

HLA class I alleles andhaplotypes

HLA class II alleles andhaplotypes Population Clinical forms Association Reference

aDRB1lowast01 DQB1lowast0303 Venezuela Chronic phase Protection [57]aDRB1lowast1501 CCC Protection [57]aDRB1lowast08 CCC Susceptibility [57]aDRB1lowast01 DQB1lowast0501 CCC Susceptibility [57 58]aDPB1lowast0401aDPB1lowast0401ndashlowast2301aDPB1lowast0401ndashlowast3901 haplotypes CCC Susceptibility [58]

bClowast03 CCC Susceptibility [59]aHLA-B40-Cw3 haplotype Chile CCC Protection [60 61]bHLA-Alowast30 Brazil All clinical form Susceptibility [63]

bDQB1lowast06 All clinical form Protection [63]bDR2 Chronic phase Susceptibility [64]

No association [65]bDRB1lowast14-DQB1lowast0301 haplotype Peru Infection Protection [66]

bHLA-B39 bHLA-DR4 Mexico Infection Susceptibility [67]bHLA-B35 bHLA-DR16 CCC SusceptibilitybHLA-A68 CCC Protection

bDRB1lowast0409 and lowast1503 Argentina Infection Susceptibility [68 69]bDRB1lowast1103 Infection Protection [69]bDRB1lowast1503 CCC Susceptibility [69]

bHLA-Blowast1402 bHLA-DRB1lowast01 Bolivian DG or mixed Protection [70]bHLA-DRB1lowast01-Blowast14-MICAlowast011haplotype Infection Protection [70]

bHLA-B35-MICA-A5haplotype Guatemala CCC Susceptibility [79]

bA31 and B39 bDR8 Latin American mestizos CCC Susceptibility [62]bDR4 DR5 DQ1 DQ3 CCC Protection

a119875 value le 005 or b

119875119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

I chain-related genes A and B) thatmay be involved in diseasepathogenesis

TheMICAmolecules are recognised by lymphocytes T120574120575lymphocytes T120572120573 CD8+ and NK cells via their receptorsNKG2D present on their surfaces in association with theDAP10 molecule an adapter protein membrane [71 72] Thiscomplex NKG2D-MICA activates the phosphorylation oftyrosine residues of themolecule DAP10 triggering a cascadeof cell signalling that ends with the process of cell lysis of thetarget cells [72] A study by Steinle et al [73] showed thatchanging a single amino acidmdasha methionine for a valine atposition 129 of the1205722 domain of the heavy chainmdashcategorisesthe MICA as strong (MICA-129met) and weak (MICA-129val) ligands of NKG2D affecting the activation of NK cells

MICA and MICB are weakly expressed on healthy cellsbut their expression is induced in response to cellular stressin many cell types including epithelial cells fibroblastskeratinocytes endothelial cells and monocytes [74ndash77]

The polymorphism of MICA may be involved in sus-ceptibility to various diseases but it has been suggestedthat this association may be secondary due to the strong

linkage disequilibrium with HLA-B alleles Groh et al [78]found that MICAlowast011 which was closely linked to HLA-Blowast14 and DRB1lowast01 might stimulate T120574120575 cells in the gutmucosa a phenomenon that could relate to megacolonIn Chagas disease the same HLA-DRB1lowast01-Blowast14-MICAlowast011haplotype was associated with resistance against the chronicform [70] MICA-A5 and HLA-B35 synergistically enhancedsusceptibility to CCC [79]

24 Association of KIR Genes and Their HLA Ligands withChagas Disease Other receptors of NK cells that recogniseHLA class I molecules present on the target cells includedKIR (killer cell immunoglobulin-like receptor) [80 81] KIRreceptors are glycoproteins that belong to the immunoglobu-lin superfamily and which are also found in some subpopu-lations of T-cells [82] KIR genes are clustered in the 19q134region and are characterised by both allelic (high numbersof variants) and haplotypic (different numbers of genes forinhibitory and activating receptors on individual chromo-somes) polymorphismsThe specific KIR-HLA combinationsmay regulate NK cell-mediated immunity against infectious

BioMed Research International 7

Table 2 Polymorphisms in cytokines genes and their association with Chagas disease

Geneallelegenotype Population Clinical form Association ReferenceTNFA minus308 minus244 minus236and TNFB Peru Infection and CCC No association [106]

bTNF minus308A Mexico Infection and CCC Susceptibility [108]TNF minus308A Brazil CCC No association [107]aTNF minus238A Brazil Infection Susceptibility [109]aTNF minus1031C and minus308A Colombia CCC Susceptibility [110]aTNFA minus1031TT andminus308GG Colombia CCC Protection [110]aTNFa2 TNFa7 TNFa8TNFb2 TNFb4 TNFd5TNFd7 TNFe2

Brazil CCC DG or mixed Protection [111]

aTNFb7 and TNFd3 Brazil CCC and mixed Susceptibility [111]aTNFa2 Brazil CCC Susceptibility [112]bLTA +80C and LTA +252G Brazil CCC Susceptibility [113]bLTA +80A +252Ahaplotype Brazil CCC Protection [113]

IL6 minus174GC PeruColombia Infection No association [114]bIL minus1RN4CC Mexico CCC Susceptibility [115]bIL1B +5810G allele andIL1B minus31 +395 CT genotype Colombia CCC Susceptibility [116]

aIL10 minus1082A and minus1082AA Brazil CCC Susceptibility [119]IL10 Colombia Infection No association [120]aIFNG +874A and +874AA Colombia Infection Susceptibility [122]aIL4 minus590T Bolivia Infection Protection [124]aIL4RA +148AA CCC Susceptibility [120]aTGFB110C and CC PeruColombia Infection Susceptibility [126]bIL12B 31015840 UTR C and CC Colombia CCC Susceptibility [127]aCXCL9CC and CXCL10GG Brazil CCC Protection [129]CCR5CC CCC Susceptibility [129]abCCR5 minus2554T minus2733G59029G 59029AG59029GG

PeruColombiaVenezuela CCC Susceptibility [130ndash132]

aCCL2 minus2518A and AA Brazil CCC Susceptibility [133]aBAT1 22C 348C Brazil CCC Susceptibility [134]a119875 value le 005 b119875

119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

pathogens and contribute to diverse susceptibility to diseasesand other clinical situations

Several studies have shown the participation ofKIR genesand their ligands in infectious diseases [83ndash89] autoimmuneor inflammatory diseases [90ndash92] cancer [93ndash95] and in thesuccess of transplantation [96] However there are no dataavailable on the role ofKIR genes in the immunopathogenesisof Chagas disease

25 Association of Polymorphisms in Cytokine Genes withChagas Disease Immunomodulatory cytokines secreted byT-cells and macrophages are molecules that act as mediatorsof inflammation and immune response These moleculesare key components in the pathogenesis of many diseasesincluding infectious diseases cancer metabolic disorders

autoimmunity and inflammatory conditions The cytokinesare important for parasitic control and are involved in thegenesis of lesions [97]

It is known that the production of some cytokines isunder genetic control and is influenced by polymorphisms inseveral cytokine genes SNPs ormicrosatellitesmainly locatedin regulatory regions may affect gene transcription and causeinterindividual variations Some of these polymorphismsinfluence the level of cytokine production which can conferflexibility in the immune response [98ndash101] Thus the pres-ence of certain alleles may influence the course of bacterialand viral infections [102 103] and confer susceptibility orresistance to autoimmune disease [104] SNPs in cytokinegenes have been described as important genetic factors in theoccurrence of different clinical forms of Chagas disease The

8 BioMed Research International

genetic susceptibility of single nucleotide polymorphisms incytokine genes to human Chagas disease was reviewed [105]The cytokines polymorphisms associatedwithChagas diseaseare summarized in Table 2

Proinflammatory cytokines play a key role in the develop-ment of CCC Aiming to investigate the influence of theTNF polymorphisms on Chagas disease TNFA (posi-tions minus308 rs1800629 minus244 rs673 minus238 rs361525 andminus1031 rs1799964) and TNFB genotypes have been inter-rogated No significant differences were observed withthese alleles or haplotypes between patients and controls in aPeruvian population [106]TNF-308A alsowas not associatedwith CCC in Brazilian patients [107] However the sameSNP could be directly involved in the genetic susceptibilityof the chronic phase and CCC in a Mexican population[108] Another study also in Brazilian patients suggestedthat allele TNF-238A which correlates with production ofsignificantly higher levels of TNF-120572 could influence thesusceptibility to infection [109] The TNF-1031C and -308Aalleles were significantly associated with the development ofCCC whereas the TNF-1031TT and -308GG genotypes wereassociated with lower risk to develop CCC in a Colombianpopulation [110] Regarding the TNF gene microsatellite tenalleles were associated with Chagas disease in the Brazilianpopulation eight of them correlate with susceptibility(TNFa2 TNFa7 TNFa8 TNFb2 TNFb4 TNFd5 TNFd7and TNFe2) and two with protection (TNFb7 and TNFd3)against the development of the disease [111] Previously theoccurrence of the TNFa2 microsatellite was correlated withreduced survival in severe cardiomyopathy [112] Despite thecontroversial results these data suggest the involvement ofTNF in the course of Chagas disease

Clinical genetic and epidemiological studies have linkedlymphotoxin-120572 (LTA) a proinflammatory cytokine to coro-nary artery disease and myocardial infarction In BrazilianCCC patients homozygosity with respect to the LTA+80C(rs2239704) and LTA+252G (rs909253) alleles was signifi-cantly more frequent and was associated with susceptibil-ity and the haplotype LTA+80A+252A was associated withprotection against CCC Furthermore homozygosity for theLTA+80A allele correlated with the lowest levels of plasmaticTNF-120572 [113]

It appears that IL6 gene polymorphism does not con-tribute to susceptibility in the clinical manifestations ofChagas disease In a study in two independent populationsof Colombia and Peru no difference was observed for IL6-174GC (rs1800795) between Chagas disease and controls orbetween asymptomatic patients and CCC [114]

Some IL1B alleles and haplotypes have been associatedwith susceptibility to inflammatory autoimmune and infec-tious diseases The IL1B-511(rs16944) IL1F103 (rs3811058)IL1RN4 (rs419598) IL1RN 61 (rs315952) and IL-1RN 62(rs315951) polymorphisms were analysed in Chagas diseaseand IL-1RN4CC genotype was clearly associated with Tcruzi infection and CCC development [115] The IL1B+5810G(rs1143633) allele and the haplotype IL1B-31 (rs1143627)+3954(rs1143634)CT were associatedwith an increased risk of CCC[116] Therefore these studies suggest that IL1 gene clusterpolymorphisms may play a relevant role in the susceptibility

to development of CCC and that the effect of IL1B gene onchagasic cardiomyopathy predisposition is dose dependent[116]

IL-10 and INF-120574 production by T cells promotes T cruzicontrol and protects against fatal acute myocarditis [115ndash118]The SNP IL10-1082 (rs1800896) A allele which is associatedwith a lower expression of IL-10 had higher frequency inCCC Brazilian patients when compared to the asymptomaticgroup [119]However inColombian patients no differences inallele frequency and haplotype of the IL10 genewere observedin symptomatic and asymptomatic patients [120] Linkagedisequilibrium analysis on microsatellite loci suggests epis-tasis between MHC and IL-10 on Chagas disease suscep-tibilityresistance [121] The frequency of the IFNG+874AA(rs62559044) which is associated with reduced productionof INF-120574 was increased in the Colombian patients suggestingthat this SNP may be involved in susceptibility but not in theprogression of Chagas disease [122]

IL-4 is described as a prototypical anti-inflammatorycytokine It can modulate the host and parasite survivals thatdepend on a fine balance betweenTh1 responses on one handit will control parasitism and on the other hand enhanceheart inflammation throughout the course of the infection[123] In a Bolivian population SNP IL4-590 (rs2243250)T allele was associated with protection against T cruziinfection [124] although in another study only the IL4RA(IL-4 receptor-120572 rs147781) +148AA genotype showed a weakassociation with the development of CCC [120]

TGF-120573 plays a pivotal role in Chagas disease not onlyin the development of chagasic cardiomyopathy but also inmany stages of the T cruzi life cycle and survival in the hostcell environment through regulation of (i) parasite invasionof heart cells (ii) an intracellular parasite cycle (iii) inflam-mation and immune response (iv) heart fibrosis and remod-elling and (v) gap junction modulation and heart conduc-tion [125] Several SNPs in the TGFB1 gene that may affectcytokine production have been described A significant dif-ference in the distribution of the TGFB1 10 (rs1982073) T andC alleles between patients and healthy controls was observedin the Peruvian and Colombian populations TGFB1 10CCthe high producer genotype was increased in patients of bothpopulations [126]

The IL-12 family of cytokines can influence Th17 andthe production of IL-17 and INF-120574 The SNPs rs3212227 inthe 31015840UTR of the gene IL12B were investigated and IL12B31015840UTR C allele and CC genotype were significantly increasedamong CCC patients when compared to asymptomatic indi-viduals [127]

MIF (macrophage migration inhibitory factor) minus173Callele and CC genotype were related to the major risk ofChagas disease in the Colombian and Peruvian populations[128]

Some chemokines also had been associated with thedevelopment of CCC CXCL9 CC (rs10336) and CXCL10GG (rs3921) genotypes were less frequent and CCR5 CC(rs1799988) was more frequent in patients with left ven-tricular dysfunction compared with patients without thisdysfunction and may indicate that CXCL9 and CXCL10 aremaster regulators of myocardial inflammatory cell migration

BioMed Research International 9

perhaps affecting clinical progression to the life-threateningform of CCC [129] Some SNPs of CCR5 gene were associ-ated with the development of severe cardiomyopathy in anendemic area of Colombia Peru and Venezuela [130ndash132]

In the Brazilian population BAT1 (HLA-B associatedtranscript 1) C allele and CC genotype at positions 22 CGand minus348 CT were associated with risk of cardiomyopathy[133] In the same population MCP-1 (monocyte chemo-attractant protein-1) geneCCL2-2518A allele (rs1024611) andthe CCL2-2518 AA genotype correlate with susceptibility tochronic cardiomyopathy [134] BAT1 MCP-1 and LTA maybe involved in the pathogenesis of cardiac Chagas disease

Despite the controversial results these data suggest theinvolvement of cytokines in the course of Chagas diseaseThebalance between TH1TH2T regulatory cytokines has differ-ent and opposing influences on the likelihood of infectionwith T cruzi and on the clinical course of the Chagas disease

3 Concluding Remarks

Many genetic linkages and association studies have attemptedto identify genetic variations that are involved in immuno-pathogenesis of Chagas disease However causal genetic vari-ants underlying susceptibility remain unknown due to com-plexity of parasite and host Susceptibilityresistance to Cha-gas disease involves multiple genetic variants functioningjointly each with small or moderate effects Immunologicalmechanisms protect against the disease but contribute toaggression and tissue damage Genome wide associationstudies (GWAS) and next generation sequencing (NGS) atpresent lacking in Chagas disease may help identifying novelgenetic polymorphisms with genome scale associations

The impact of pathogens on host cell functions as wellas genetic markers that were significantly associated withdisease was found on schistosomiasis [135] ascariasis [136]leprosy [137] tuberculosis [138 139] malaria [140] dengue[141] hepatitis [142 143] andHIV-1 [144ndash147] In Chagas dis-ease the 2590T allele (rs2243250) polymorphism in the pro-moter region of IL4 gene is a marker for IL4 haplotypes likelyassociated with protection against T cruzi infection [124]

The identification of the specific genes influencing Tcruzi infection and Chagas disease through genome scanstechniques could offer a particular opportunity for mappinggenes of susceptibility or resistance Further studies are neces-sary to clarify the relationship between genotype and devel-opment of disease and its clinical outcomes

The characterisation of the susceptibility genes and theirvariants has important implications not only for a betterunderstanding of disease pathogenesis but also for the con-trol and development of new therapeutic strategies for infec-tious diseases

References

[1] C Chagas ldquoNova tripanozomiaze humana Estudos sobre amorfologia e o ciclo evolutivo do Schizotrypanum cruzi n genn sp Agente etiologico Agente etiologico de uma nova entidademorbida para o homemrdquoMemorias do Instituto Oswaldo Cruzvol 1 pp 159ndash218 1909

[2] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[3] L O Andrade C R S Machado E Chiari S D J Penaand A M Macedo ldquoDifferential tissue distribution of diverseclones of Trypanosoma cruzi in infected micerdquo Molecular andBiochemical Parasitology vol 100 no 2 pp 163ndash172 1999

[4] World Health Organization (2012) Chagas disease (Americantrypanosomiasis) Fact Sheet No 340

[5] L V Kirchhoff ldquoChanging epidemiology and approaches totherapy for Chagas diseaserdquo Current Infectious Disease Reportsvol 5 no 1 pp 59ndash65 2003

[6] C Hoare ldquoThe trypanosomes of mammalsrdquo Journal of SmallAnimal Practice vol 13 pp 671ndash672 1972

[7] C J Schofield ldquoOverview evolution of the triatominaerdquo in Pro-ceedings of the 2nd International Workshop on Population Gen-etics and Control of Triatominae C J Schofield and C PonceEds INDRE Tegucigalpa Honduras 1998

[8] F Rothhammer M J Allison L Nunez V Standen and BArriaza ldquoChagas disease in pre-Columbian South AmericardquoAmerican Journal of Physical Anthropology vol 68 no 4 pp495ndash498 1985

[9] J R Coura ldquoChagas disease what is known and what isneededmdasha background articlerdquoMemorias do Instituto OswaldoCruz vol 102 no 1 pp 113ndash122 2007

[10] A C Aufderheide W Salo M Madden et al ldquoA 9000-yearrecord of Chagas diseaserdquo Proceedings of the National Academyof Sciences of USA vol 101 no 7 pp 2034ndash2039 2004

[11] Y Carlier J C PDias AO LuquettiMHonteberye F Torricoand C Truyens ldquoTrypanosomiase americaine ou maladie deChagasrdquo in Encyclopedie Medico Chirurgicale Elsevier ParisFrence 2002

[12] W B Bean ldquoThe illness of Charles DarwinrdquoTheAmerican Jour-nal of Medicine vol 65 no 4 pp 572ndash574 1978

[13] F Koberle ldquo50 Years of Chagasrsquo diseaserdquoMunchener Medizinis-che Wochenschrift vol 99 pp 1193ndash1198 1957

[14] A Moncayo and M I Ortiz Yanine ldquoAn update on Chagasdisease (humanAmerican trypanosomiasis)rdquoAnnals of TropicalMedicine and Parasitology vol 100 no 8 pp 663ndash677 2006

[15] G A Schmunis ldquoEpidemiology of Chagas disease in non-ende-mic countries the role of internationalmigrationrdquoMemorias doInstituto Oswaldo Cruz vol 102 no 1 pp 75ndash85 2007

[16] G A Schmunis and Z E Yadon ldquoChagas disease a LatinAmerican health problem becoming a world health problemrdquoActa Tropica vol 115 no 1-2 pp 14ndash21 2010

[17] J R Coura and P A Vinas ldquoChagas disease a new worldwidechallengerdquo Nature vol 465 no 7301 pp S6ndashS7 2010

[18] A F Henao-Martınez D A Schwart and I V Yang ldquoChagasiccardiomyopathy from acute to chronic is this mediated byhost susceptibility factorsrdquo Transactions of the Royal Society ofTropicalMedicine andHygiene vol 106 no 9 pp 521mdash527 2012

[19] D P Neves A L Melo and O Genaro Eds ParasitologiaHumana Atheneu Sao Paulo Brazil 2005

[20] D Born R E S Acha and M Ferraz ldquoPregnancy and Chagasrsquodiseaserdquo Journal of the American College of Cardiology vol 31p 421 1998

[21] E L P Camandaroba C M Pinheiro Lima and S G AndradeldquoOral transmission of Chagas disease importance of Trypano-soma cruzi biodeme in the intragastric experimental infectionrdquoRevista do Instituto de Medicina Tropical de Sao Paulo vol 44no 2 pp 97ndash103 2002

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Page 6: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

6 BioMed Research International

Table 1 Alleles and haplotypes HLA associated with Chagas disease

HLA class I alleles andhaplotypes

HLA class II alleles andhaplotypes Population Clinical forms Association Reference

aDRB1lowast01 DQB1lowast0303 Venezuela Chronic phase Protection [57]aDRB1lowast1501 CCC Protection [57]aDRB1lowast08 CCC Susceptibility [57]aDRB1lowast01 DQB1lowast0501 CCC Susceptibility [57 58]aDPB1lowast0401aDPB1lowast0401ndashlowast2301aDPB1lowast0401ndashlowast3901 haplotypes CCC Susceptibility [58]

bClowast03 CCC Susceptibility [59]aHLA-B40-Cw3 haplotype Chile CCC Protection [60 61]bHLA-Alowast30 Brazil All clinical form Susceptibility [63]

bDQB1lowast06 All clinical form Protection [63]bDR2 Chronic phase Susceptibility [64]

No association [65]bDRB1lowast14-DQB1lowast0301 haplotype Peru Infection Protection [66]

bHLA-B39 bHLA-DR4 Mexico Infection Susceptibility [67]bHLA-B35 bHLA-DR16 CCC SusceptibilitybHLA-A68 CCC Protection

bDRB1lowast0409 and lowast1503 Argentina Infection Susceptibility [68 69]bDRB1lowast1103 Infection Protection [69]bDRB1lowast1503 CCC Susceptibility [69]

bHLA-Blowast1402 bHLA-DRB1lowast01 Bolivian DG or mixed Protection [70]bHLA-DRB1lowast01-Blowast14-MICAlowast011haplotype Infection Protection [70]

bHLA-B35-MICA-A5haplotype Guatemala CCC Susceptibility [79]

bA31 and B39 bDR8 Latin American mestizos CCC Susceptibility [62]bDR4 DR5 DQ1 DQ3 CCC Protection

a119875 value le 005 or b

119875119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

I chain-related genes A and B) thatmay be involved in diseasepathogenesis

TheMICAmolecules are recognised by lymphocytes T120574120575lymphocytes T120572120573 CD8+ and NK cells via their receptorsNKG2D present on their surfaces in association with theDAP10 molecule an adapter protein membrane [71 72] Thiscomplex NKG2D-MICA activates the phosphorylation oftyrosine residues of themolecule DAP10 triggering a cascadeof cell signalling that ends with the process of cell lysis of thetarget cells [72] A study by Steinle et al [73] showed thatchanging a single amino acidmdasha methionine for a valine atposition 129 of the1205722 domain of the heavy chainmdashcategorisesthe MICA as strong (MICA-129met) and weak (MICA-129val) ligands of NKG2D affecting the activation of NK cells

MICA and MICB are weakly expressed on healthy cellsbut their expression is induced in response to cellular stressin many cell types including epithelial cells fibroblastskeratinocytes endothelial cells and monocytes [74ndash77]

The polymorphism of MICA may be involved in sus-ceptibility to various diseases but it has been suggestedthat this association may be secondary due to the strong

linkage disequilibrium with HLA-B alleles Groh et al [78]found that MICAlowast011 which was closely linked to HLA-Blowast14 and DRB1lowast01 might stimulate T120574120575 cells in the gutmucosa a phenomenon that could relate to megacolonIn Chagas disease the same HLA-DRB1lowast01-Blowast14-MICAlowast011haplotype was associated with resistance against the chronicform [70] MICA-A5 and HLA-B35 synergistically enhancedsusceptibility to CCC [79]

24 Association of KIR Genes and Their HLA Ligands withChagas Disease Other receptors of NK cells that recogniseHLA class I molecules present on the target cells includedKIR (killer cell immunoglobulin-like receptor) [80 81] KIRreceptors are glycoproteins that belong to the immunoglobu-lin superfamily and which are also found in some subpopu-lations of T-cells [82] KIR genes are clustered in the 19q134region and are characterised by both allelic (high numbersof variants) and haplotypic (different numbers of genes forinhibitory and activating receptors on individual chromo-somes) polymorphismsThe specific KIR-HLA combinationsmay regulate NK cell-mediated immunity against infectious

BioMed Research International 7

Table 2 Polymorphisms in cytokines genes and their association with Chagas disease

Geneallelegenotype Population Clinical form Association ReferenceTNFA minus308 minus244 minus236and TNFB Peru Infection and CCC No association [106]

bTNF minus308A Mexico Infection and CCC Susceptibility [108]TNF minus308A Brazil CCC No association [107]aTNF minus238A Brazil Infection Susceptibility [109]aTNF minus1031C and minus308A Colombia CCC Susceptibility [110]aTNFA minus1031TT andminus308GG Colombia CCC Protection [110]aTNFa2 TNFa7 TNFa8TNFb2 TNFb4 TNFd5TNFd7 TNFe2

Brazil CCC DG or mixed Protection [111]

aTNFb7 and TNFd3 Brazil CCC and mixed Susceptibility [111]aTNFa2 Brazil CCC Susceptibility [112]bLTA +80C and LTA +252G Brazil CCC Susceptibility [113]bLTA +80A +252Ahaplotype Brazil CCC Protection [113]

IL6 minus174GC PeruColombia Infection No association [114]bIL minus1RN4CC Mexico CCC Susceptibility [115]bIL1B +5810G allele andIL1B minus31 +395 CT genotype Colombia CCC Susceptibility [116]

aIL10 minus1082A and minus1082AA Brazil CCC Susceptibility [119]IL10 Colombia Infection No association [120]aIFNG +874A and +874AA Colombia Infection Susceptibility [122]aIL4 minus590T Bolivia Infection Protection [124]aIL4RA +148AA CCC Susceptibility [120]aTGFB110C and CC PeruColombia Infection Susceptibility [126]bIL12B 31015840 UTR C and CC Colombia CCC Susceptibility [127]aCXCL9CC and CXCL10GG Brazil CCC Protection [129]CCR5CC CCC Susceptibility [129]abCCR5 minus2554T minus2733G59029G 59029AG59029GG

PeruColombiaVenezuela CCC Susceptibility [130ndash132]

aCCL2 minus2518A and AA Brazil CCC Susceptibility [133]aBAT1 22C 348C Brazil CCC Susceptibility [134]a119875 value le 005 b119875

119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

pathogens and contribute to diverse susceptibility to diseasesand other clinical situations

Several studies have shown the participation ofKIR genesand their ligands in infectious diseases [83ndash89] autoimmuneor inflammatory diseases [90ndash92] cancer [93ndash95] and in thesuccess of transplantation [96] However there are no dataavailable on the role ofKIR genes in the immunopathogenesisof Chagas disease

25 Association of Polymorphisms in Cytokine Genes withChagas Disease Immunomodulatory cytokines secreted byT-cells and macrophages are molecules that act as mediatorsof inflammation and immune response These moleculesare key components in the pathogenesis of many diseasesincluding infectious diseases cancer metabolic disorders

autoimmunity and inflammatory conditions The cytokinesare important for parasitic control and are involved in thegenesis of lesions [97]

It is known that the production of some cytokines isunder genetic control and is influenced by polymorphisms inseveral cytokine genes SNPs ormicrosatellitesmainly locatedin regulatory regions may affect gene transcription and causeinterindividual variations Some of these polymorphismsinfluence the level of cytokine production which can conferflexibility in the immune response [98ndash101] Thus the pres-ence of certain alleles may influence the course of bacterialand viral infections [102 103] and confer susceptibility orresistance to autoimmune disease [104] SNPs in cytokinegenes have been described as important genetic factors in theoccurrence of different clinical forms of Chagas disease The

8 BioMed Research International

genetic susceptibility of single nucleotide polymorphisms incytokine genes to human Chagas disease was reviewed [105]The cytokines polymorphisms associatedwithChagas diseaseare summarized in Table 2

Proinflammatory cytokines play a key role in the develop-ment of CCC Aiming to investigate the influence of theTNF polymorphisms on Chagas disease TNFA (posi-tions minus308 rs1800629 minus244 rs673 minus238 rs361525 andminus1031 rs1799964) and TNFB genotypes have been inter-rogated No significant differences were observed withthese alleles or haplotypes between patients and controls in aPeruvian population [106]TNF-308A alsowas not associatedwith CCC in Brazilian patients [107] However the sameSNP could be directly involved in the genetic susceptibilityof the chronic phase and CCC in a Mexican population[108] Another study also in Brazilian patients suggestedthat allele TNF-238A which correlates with production ofsignificantly higher levels of TNF-120572 could influence thesusceptibility to infection [109] The TNF-1031C and -308Aalleles were significantly associated with the development ofCCC whereas the TNF-1031TT and -308GG genotypes wereassociated with lower risk to develop CCC in a Colombianpopulation [110] Regarding the TNF gene microsatellite tenalleles were associated with Chagas disease in the Brazilianpopulation eight of them correlate with susceptibility(TNFa2 TNFa7 TNFa8 TNFb2 TNFb4 TNFd5 TNFd7and TNFe2) and two with protection (TNFb7 and TNFd3)against the development of the disease [111] Previously theoccurrence of the TNFa2 microsatellite was correlated withreduced survival in severe cardiomyopathy [112] Despite thecontroversial results these data suggest the involvement ofTNF in the course of Chagas disease

Clinical genetic and epidemiological studies have linkedlymphotoxin-120572 (LTA) a proinflammatory cytokine to coro-nary artery disease and myocardial infarction In BrazilianCCC patients homozygosity with respect to the LTA+80C(rs2239704) and LTA+252G (rs909253) alleles was signifi-cantly more frequent and was associated with susceptibil-ity and the haplotype LTA+80A+252A was associated withprotection against CCC Furthermore homozygosity for theLTA+80A allele correlated with the lowest levels of plasmaticTNF-120572 [113]

It appears that IL6 gene polymorphism does not con-tribute to susceptibility in the clinical manifestations ofChagas disease In a study in two independent populationsof Colombia and Peru no difference was observed for IL6-174GC (rs1800795) between Chagas disease and controls orbetween asymptomatic patients and CCC [114]

Some IL1B alleles and haplotypes have been associatedwith susceptibility to inflammatory autoimmune and infec-tious diseases The IL1B-511(rs16944) IL1F103 (rs3811058)IL1RN4 (rs419598) IL1RN 61 (rs315952) and IL-1RN 62(rs315951) polymorphisms were analysed in Chagas diseaseand IL-1RN4CC genotype was clearly associated with Tcruzi infection and CCC development [115] The IL1B+5810G(rs1143633) allele and the haplotype IL1B-31 (rs1143627)+3954(rs1143634)CT were associatedwith an increased risk of CCC[116] Therefore these studies suggest that IL1 gene clusterpolymorphisms may play a relevant role in the susceptibility

to development of CCC and that the effect of IL1B gene onchagasic cardiomyopathy predisposition is dose dependent[116]

IL-10 and INF-120574 production by T cells promotes T cruzicontrol and protects against fatal acute myocarditis [115ndash118]The SNP IL10-1082 (rs1800896) A allele which is associatedwith a lower expression of IL-10 had higher frequency inCCC Brazilian patients when compared to the asymptomaticgroup [119]However inColombian patients no differences inallele frequency and haplotype of the IL10 genewere observedin symptomatic and asymptomatic patients [120] Linkagedisequilibrium analysis on microsatellite loci suggests epis-tasis between MHC and IL-10 on Chagas disease suscep-tibilityresistance [121] The frequency of the IFNG+874AA(rs62559044) which is associated with reduced productionof INF-120574 was increased in the Colombian patients suggestingthat this SNP may be involved in susceptibility but not in theprogression of Chagas disease [122]

IL-4 is described as a prototypical anti-inflammatorycytokine It can modulate the host and parasite survivals thatdepend on a fine balance betweenTh1 responses on one handit will control parasitism and on the other hand enhanceheart inflammation throughout the course of the infection[123] In a Bolivian population SNP IL4-590 (rs2243250)T allele was associated with protection against T cruziinfection [124] although in another study only the IL4RA(IL-4 receptor-120572 rs147781) +148AA genotype showed a weakassociation with the development of CCC [120]

TGF-120573 plays a pivotal role in Chagas disease not onlyin the development of chagasic cardiomyopathy but also inmany stages of the T cruzi life cycle and survival in the hostcell environment through regulation of (i) parasite invasionof heart cells (ii) an intracellular parasite cycle (iii) inflam-mation and immune response (iv) heart fibrosis and remod-elling and (v) gap junction modulation and heart conduc-tion [125] Several SNPs in the TGFB1 gene that may affectcytokine production have been described A significant dif-ference in the distribution of the TGFB1 10 (rs1982073) T andC alleles between patients and healthy controls was observedin the Peruvian and Colombian populations TGFB1 10CCthe high producer genotype was increased in patients of bothpopulations [126]

The IL-12 family of cytokines can influence Th17 andthe production of IL-17 and INF-120574 The SNPs rs3212227 inthe 31015840UTR of the gene IL12B were investigated and IL12B31015840UTR C allele and CC genotype were significantly increasedamong CCC patients when compared to asymptomatic indi-viduals [127]

MIF (macrophage migration inhibitory factor) minus173Callele and CC genotype were related to the major risk ofChagas disease in the Colombian and Peruvian populations[128]

Some chemokines also had been associated with thedevelopment of CCC CXCL9 CC (rs10336) and CXCL10GG (rs3921) genotypes were less frequent and CCR5 CC(rs1799988) was more frequent in patients with left ven-tricular dysfunction compared with patients without thisdysfunction and may indicate that CXCL9 and CXCL10 aremaster regulators of myocardial inflammatory cell migration

BioMed Research International 9

perhaps affecting clinical progression to the life-threateningform of CCC [129] Some SNPs of CCR5 gene were associ-ated with the development of severe cardiomyopathy in anendemic area of Colombia Peru and Venezuela [130ndash132]

In the Brazilian population BAT1 (HLA-B associatedtranscript 1) C allele and CC genotype at positions 22 CGand minus348 CT were associated with risk of cardiomyopathy[133] In the same population MCP-1 (monocyte chemo-attractant protein-1) geneCCL2-2518A allele (rs1024611) andthe CCL2-2518 AA genotype correlate with susceptibility tochronic cardiomyopathy [134] BAT1 MCP-1 and LTA maybe involved in the pathogenesis of cardiac Chagas disease

Despite the controversial results these data suggest theinvolvement of cytokines in the course of Chagas diseaseThebalance between TH1TH2T regulatory cytokines has differ-ent and opposing influences on the likelihood of infectionwith T cruzi and on the clinical course of the Chagas disease

3 Concluding Remarks

Many genetic linkages and association studies have attemptedto identify genetic variations that are involved in immuno-pathogenesis of Chagas disease However causal genetic vari-ants underlying susceptibility remain unknown due to com-plexity of parasite and host Susceptibilityresistance to Cha-gas disease involves multiple genetic variants functioningjointly each with small or moderate effects Immunologicalmechanisms protect against the disease but contribute toaggression and tissue damage Genome wide associationstudies (GWAS) and next generation sequencing (NGS) atpresent lacking in Chagas disease may help identifying novelgenetic polymorphisms with genome scale associations

The impact of pathogens on host cell functions as wellas genetic markers that were significantly associated withdisease was found on schistosomiasis [135] ascariasis [136]leprosy [137] tuberculosis [138 139] malaria [140] dengue[141] hepatitis [142 143] andHIV-1 [144ndash147] In Chagas dis-ease the 2590T allele (rs2243250) polymorphism in the pro-moter region of IL4 gene is a marker for IL4 haplotypes likelyassociated with protection against T cruzi infection [124]

The identification of the specific genes influencing Tcruzi infection and Chagas disease through genome scanstechniques could offer a particular opportunity for mappinggenes of susceptibility or resistance Further studies are neces-sary to clarify the relationship between genotype and devel-opment of disease and its clinical outcomes

The characterisation of the susceptibility genes and theirvariants has important implications not only for a betterunderstanding of disease pathogenesis but also for the con-trol and development of new therapeutic strategies for infec-tious diseases

References

[1] C Chagas ldquoNova tripanozomiaze humana Estudos sobre amorfologia e o ciclo evolutivo do Schizotrypanum cruzi n genn sp Agente etiologico Agente etiologico de uma nova entidademorbida para o homemrdquoMemorias do Instituto Oswaldo Cruzvol 1 pp 159ndash218 1909

[2] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[3] L O Andrade C R S Machado E Chiari S D J Penaand A M Macedo ldquoDifferential tissue distribution of diverseclones of Trypanosoma cruzi in infected micerdquo Molecular andBiochemical Parasitology vol 100 no 2 pp 163ndash172 1999

[4] World Health Organization (2012) Chagas disease (Americantrypanosomiasis) Fact Sheet No 340

[5] L V Kirchhoff ldquoChanging epidemiology and approaches totherapy for Chagas diseaserdquo Current Infectious Disease Reportsvol 5 no 1 pp 59ndash65 2003

[6] C Hoare ldquoThe trypanosomes of mammalsrdquo Journal of SmallAnimal Practice vol 13 pp 671ndash672 1972

[7] C J Schofield ldquoOverview evolution of the triatominaerdquo in Pro-ceedings of the 2nd International Workshop on Population Gen-etics and Control of Triatominae C J Schofield and C PonceEds INDRE Tegucigalpa Honduras 1998

[8] F Rothhammer M J Allison L Nunez V Standen and BArriaza ldquoChagas disease in pre-Columbian South AmericardquoAmerican Journal of Physical Anthropology vol 68 no 4 pp495ndash498 1985

[9] J R Coura ldquoChagas disease what is known and what isneededmdasha background articlerdquoMemorias do Instituto OswaldoCruz vol 102 no 1 pp 113ndash122 2007

[10] A C Aufderheide W Salo M Madden et al ldquoA 9000-yearrecord of Chagas diseaserdquo Proceedings of the National Academyof Sciences of USA vol 101 no 7 pp 2034ndash2039 2004

[11] Y Carlier J C PDias AO LuquettiMHonteberye F Torricoand C Truyens ldquoTrypanosomiase americaine ou maladie deChagasrdquo in Encyclopedie Medico Chirurgicale Elsevier ParisFrence 2002

[12] W B Bean ldquoThe illness of Charles DarwinrdquoTheAmerican Jour-nal of Medicine vol 65 no 4 pp 572ndash574 1978

[13] F Koberle ldquo50 Years of Chagasrsquo diseaserdquoMunchener Medizinis-che Wochenschrift vol 99 pp 1193ndash1198 1957

[14] A Moncayo and M I Ortiz Yanine ldquoAn update on Chagasdisease (humanAmerican trypanosomiasis)rdquoAnnals of TropicalMedicine and Parasitology vol 100 no 8 pp 663ndash677 2006

[15] G A Schmunis ldquoEpidemiology of Chagas disease in non-ende-mic countries the role of internationalmigrationrdquoMemorias doInstituto Oswaldo Cruz vol 102 no 1 pp 75ndash85 2007

[16] G A Schmunis and Z E Yadon ldquoChagas disease a LatinAmerican health problem becoming a world health problemrdquoActa Tropica vol 115 no 1-2 pp 14ndash21 2010

[17] J R Coura and P A Vinas ldquoChagas disease a new worldwidechallengerdquo Nature vol 465 no 7301 pp S6ndashS7 2010

[18] A F Henao-Martınez D A Schwart and I V Yang ldquoChagasiccardiomyopathy from acute to chronic is this mediated byhost susceptibility factorsrdquo Transactions of the Royal Society ofTropicalMedicine andHygiene vol 106 no 9 pp 521mdash527 2012

[19] D P Neves A L Melo and O Genaro Eds ParasitologiaHumana Atheneu Sao Paulo Brazil 2005

[20] D Born R E S Acha and M Ferraz ldquoPregnancy and Chagasrsquodiseaserdquo Journal of the American College of Cardiology vol 31p 421 1998

[21] E L P Camandaroba C M Pinheiro Lima and S G AndradeldquoOral transmission of Chagas disease importance of Trypano-soma cruzi biodeme in the intragastric experimental infectionrdquoRevista do Instituto de Medicina Tropical de Sao Paulo vol 44no 2 pp 97ndash103 2002

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Page 7: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

BioMed Research International 7

Table 2 Polymorphisms in cytokines genes and their association with Chagas disease

Geneallelegenotype Population Clinical form Association ReferenceTNFA minus308 minus244 minus236and TNFB Peru Infection and CCC No association [106]

bTNF minus308A Mexico Infection and CCC Susceptibility [108]TNF minus308A Brazil CCC No association [107]aTNF minus238A Brazil Infection Susceptibility [109]aTNF minus1031C and minus308A Colombia CCC Susceptibility [110]aTNFA minus1031TT andminus308GG Colombia CCC Protection [110]aTNFa2 TNFa7 TNFa8TNFb2 TNFb4 TNFd5TNFd7 TNFe2

Brazil CCC DG or mixed Protection [111]

aTNFb7 and TNFd3 Brazil CCC and mixed Susceptibility [111]aTNFa2 Brazil CCC Susceptibility [112]bLTA +80C and LTA +252G Brazil CCC Susceptibility [113]bLTA +80A +252Ahaplotype Brazil CCC Protection [113]

IL6 minus174GC PeruColombia Infection No association [114]bIL minus1RN4CC Mexico CCC Susceptibility [115]bIL1B +5810G allele andIL1B minus31 +395 CT genotype Colombia CCC Susceptibility [116]

aIL10 minus1082A and minus1082AA Brazil CCC Susceptibility [119]IL10 Colombia Infection No association [120]aIFNG +874A and +874AA Colombia Infection Susceptibility [122]aIL4 minus590T Bolivia Infection Protection [124]aIL4RA +148AA CCC Susceptibility [120]aTGFB110C and CC PeruColombia Infection Susceptibility [126]bIL12B 31015840 UTR C and CC Colombia CCC Susceptibility [127]aCXCL9CC and CXCL10GG Brazil CCC Protection [129]CCR5CC CCC Susceptibility [129]abCCR5 minus2554T minus2733G59029G 59029AG59029GG

PeruColombiaVenezuela CCC Susceptibility [130ndash132]

aCCL2 minus2518A and AA Brazil CCC Susceptibility [133]aBAT1 22C 348C Brazil CCC Susceptibility [134]a119875 value le 005 b119875

119888value le 005

CCC chronic Chagas cardiomyopathy DG digestive form mixed CCC and DG or CCC + DG

pathogens and contribute to diverse susceptibility to diseasesand other clinical situations

Several studies have shown the participation ofKIR genesand their ligands in infectious diseases [83ndash89] autoimmuneor inflammatory diseases [90ndash92] cancer [93ndash95] and in thesuccess of transplantation [96] However there are no dataavailable on the role ofKIR genes in the immunopathogenesisof Chagas disease

25 Association of Polymorphisms in Cytokine Genes withChagas Disease Immunomodulatory cytokines secreted byT-cells and macrophages are molecules that act as mediatorsof inflammation and immune response These moleculesare key components in the pathogenesis of many diseasesincluding infectious diseases cancer metabolic disorders

autoimmunity and inflammatory conditions The cytokinesare important for parasitic control and are involved in thegenesis of lesions [97]

It is known that the production of some cytokines isunder genetic control and is influenced by polymorphisms inseveral cytokine genes SNPs ormicrosatellitesmainly locatedin regulatory regions may affect gene transcription and causeinterindividual variations Some of these polymorphismsinfluence the level of cytokine production which can conferflexibility in the immune response [98ndash101] Thus the pres-ence of certain alleles may influence the course of bacterialand viral infections [102 103] and confer susceptibility orresistance to autoimmune disease [104] SNPs in cytokinegenes have been described as important genetic factors in theoccurrence of different clinical forms of Chagas disease The

8 BioMed Research International

genetic susceptibility of single nucleotide polymorphisms incytokine genes to human Chagas disease was reviewed [105]The cytokines polymorphisms associatedwithChagas diseaseare summarized in Table 2

Proinflammatory cytokines play a key role in the develop-ment of CCC Aiming to investigate the influence of theTNF polymorphisms on Chagas disease TNFA (posi-tions minus308 rs1800629 minus244 rs673 minus238 rs361525 andminus1031 rs1799964) and TNFB genotypes have been inter-rogated No significant differences were observed withthese alleles or haplotypes between patients and controls in aPeruvian population [106]TNF-308A alsowas not associatedwith CCC in Brazilian patients [107] However the sameSNP could be directly involved in the genetic susceptibilityof the chronic phase and CCC in a Mexican population[108] Another study also in Brazilian patients suggestedthat allele TNF-238A which correlates with production ofsignificantly higher levels of TNF-120572 could influence thesusceptibility to infection [109] The TNF-1031C and -308Aalleles were significantly associated with the development ofCCC whereas the TNF-1031TT and -308GG genotypes wereassociated with lower risk to develop CCC in a Colombianpopulation [110] Regarding the TNF gene microsatellite tenalleles were associated with Chagas disease in the Brazilianpopulation eight of them correlate with susceptibility(TNFa2 TNFa7 TNFa8 TNFb2 TNFb4 TNFd5 TNFd7and TNFe2) and two with protection (TNFb7 and TNFd3)against the development of the disease [111] Previously theoccurrence of the TNFa2 microsatellite was correlated withreduced survival in severe cardiomyopathy [112] Despite thecontroversial results these data suggest the involvement ofTNF in the course of Chagas disease

Clinical genetic and epidemiological studies have linkedlymphotoxin-120572 (LTA) a proinflammatory cytokine to coro-nary artery disease and myocardial infarction In BrazilianCCC patients homozygosity with respect to the LTA+80C(rs2239704) and LTA+252G (rs909253) alleles was signifi-cantly more frequent and was associated with susceptibil-ity and the haplotype LTA+80A+252A was associated withprotection against CCC Furthermore homozygosity for theLTA+80A allele correlated with the lowest levels of plasmaticTNF-120572 [113]

It appears that IL6 gene polymorphism does not con-tribute to susceptibility in the clinical manifestations ofChagas disease In a study in two independent populationsof Colombia and Peru no difference was observed for IL6-174GC (rs1800795) between Chagas disease and controls orbetween asymptomatic patients and CCC [114]

Some IL1B alleles and haplotypes have been associatedwith susceptibility to inflammatory autoimmune and infec-tious diseases The IL1B-511(rs16944) IL1F103 (rs3811058)IL1RN4 (rs419598) IL1RN 61 (rs315952) and IL-1RN 62(rs315951) polymorphisms were analysed in Chagas diseaseand IL-1RN4CC genotype was clearly associated with Tcruzi infection and CCC development [115] The IL1B+5810G(rs1143633) allele and the haplotype IL1B-31 (rs1143627)+3954(rs1143634)CT were associatedwith an increased risk of CCC[116] Therefore these studies suggest that IL1 gene clusterpolymorphisms may play a relevant role in the susceptibility

to development of CCC and that the effect of IL1B gene onchagasic cardiomyopathy predisposition is dose dependent[116]

IL-10 and INF-120574 production by T cells promotes T cruzicontrol and protects against fatal acute myocarditis [115ndash118]The SNP IL10-1082 (rs1800896) A allele which is associatedwith a lower expression of IL-10 had higher frequency inCCC Brazilian patients when compared to the asymptomaticgroup [119]However inColombian patients no differences inallele frequency and haplotype of the IL10 genewere observedin symptomatic and asymptomatic patients [120] Linkagedisequilibrium analysis on microsatellite loci suggests epis-tasis between MHC and IL-10 on Chagas disease suscep-tibilityresistance [121] The frequency of the IFNG+874AA(rs62559044) which is associated with reduced productionof INF-120574 was increased in the Colombian patients suggestingthat this SNP may be involved in susceptibility but not in theprogression of Chagas disease [122]

IL-4 is described as a prototypical anti-inflammatorycytokine It can modulate the host and parasite survivals thatdepend on a fine balance betweenTh1 responses on one handit will control parasitism and on the other hand enhanceheart inflammation throughout the course of the infection[123] In a Bolivian population SNP IL4-590 (rs2243250)T allele was associated with protection against T cruziinfection [124] although in another study only the IL4RA(IL-4 receptor-120572 rs147781) +148AA genotype showed a weakassociation with the development of CCC [120]

TGF-120573 plays a pivotal role in Chagas disease not onlyin the development of chagasic cardiomyopathy but also inmany stages of the T cruzi life cycle and survival in the hostcell environment through regulation of (i) parasite invasionof heart cells (ii) an intracellular parasite cycle (iii) inflam-mation and immune response (iv) heart fibrosis and remod-elling and (v) gap junction modulation and heart conduc-tion [125] Several SNPs in the TGFB1 gene that may affectcytokine production have been described A significant dif-ference in the distribution of the TGFB1 10 (rs1982073) T andC alleles between patients and healthy controls was observedin the Peruvian and Colombian populations TGFB1 10CCthe high producer genotype was increased in patients of bothpopulations [126]

The IL-12 family of cytokines can influence Th17 andthe production of IL-17 and INF-120574 The SNPs rs3212227 inthe 31015840UTR of the gene IL12B were investigated and IL12B31015840UTR C allele and CC genotype were significantly increasedamong CCC patients when compared to asymptomatic indi-viduals [127]

MIF (macrophage migration inhibitory factor) minus173Callele and CC genotype were related to the major risk ofChagas disease in the Colombian and Peruvian populations[128]

Some chemokines also had been associated with thedevelopment of CCC CXCL9 CC (rs10336) and CXCL10GG (rs3921) genotypes were less frequent and CCR5 CC(rs1799988) was more frequent in patients with left ven-tricular dysfunction compared with patients without thisdysfunction and may indicate that CXCL9 and CXCL10 aremaster regulators of myocardial inflammatory cell migration

BioMed Research International 9

perhaps affecting clinical progression to the life-threateningform of CCC [129] Some SNPs of CCR5 gene were associ-ated with the development of severe cardiomyopathy in anendemic area of Colombia Peru and Venezuela [130ndash132]

In the Brazilian population BAT1 (HLA-B associatedtranscript 1) C allele and CC genotype at positions 22 CGand minus348 CT were associated with risk of cardiomyopathy[133] In the same population MCP-1 (monocyte chemo-attractant protein-1) geneCCL2-2518A allele (rs1024611) andthe CCL2-2518 AA genotype correlate with susceptibility tochronic cardiomyopathy [134] BAT1 MCP-1 and LTA maybe involved in the pathogenesis of cardiac Chagas disease

Despite the controversial results these data suggest theinvolvement of cytokines in the course of Chagas diseaseThebalance between TH1TH2T regulatory cytokines has differ-ent and opposing influences on the likelihood of infectionwith T cruzi and on the clinical course of the Chagas disease

3 Concluding Remarks

Many genetic linkages and association studies have attemptedto identify genetic variations that are involved in immuno-pathogenesis of Chagas disease However causal genetic vari-ants underlying susceptibility remain unknown due to com-plexity of parasite and host Susceptibilityresistance to Cha-gas disease involves multiple genetic variants functioningjointly each with small or moderate effects Immunologicalmechanisms protect against the disease but contribute toaggression and tissue damage Genome wide associationstudies (GWAS) and next generation sequencing (NGS) atpresent lacking in Chagas disease may help identifying novelgenetic polymorphisms with genome scale associations

The impact of pathogens on host cell functions as wellas genetic markers that were significantly associated withdisease was found on schistosomiasis [135] ascariasis [136]leprosy [137] tuberculosis [138 139] malaria [140] dengue[141] hepatitis [142 143] andHIV-1 [144ndash147] In Chagas dis-ease the 2590T allele (rs2243250) polymorphism in the pro-moter region of IL4 gene is a marker for IL4 haplotypes likelyassociated with protection against T cruzi infection [124]

The identification of the specific genes influencing Tcruzi infection and Chagas disease through genome scanstechniques could offer a particular opportunity for mappinggenes of susceptibility or resistance Further studies are neces-sary to clarify the relationship between genotype and devel-opment of disease and its clinical outcomes

The characterisation of the susceptibility genes and theirvariants has important implications not only for a betterunderstanding of disease pathogenesis but also for the con-trol and development of new therapeutic strategies for infec-tious diseases

References

[1] C Chagas ldquoNova tripanozomiaze humana Estudos sobre amorfologia e o ciclo evolutivo do Schizotrypanum cruzi n genn sp Agente etiologico Agente etiologico de uma nova entidademorbida para o homemrdquoMemorias do Instituto Oswaldo Cruzvol 1 pp 159ndash218 1909

[2] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[3] L O Andrade C R S Machado E Chiari S D J Penaand A M Macedo ldquoDifferential tissue distribution of diverseclones of Trypanosoma cruzi in infected micerdquo Molecular andBiochemical Parasitology vol 100 no 2 pp 163ndash172 1999

[4] World Health Organization (2012) Chagas disease (Americantrypanosomiasis) Fact Sheet No 340

[5] L V Kirchhoff ldquoChanging epidemiology and approaches totherapy for Chagas diseaserdquo Current Infectious Disease Reportsvol 5 no 1 pp 59ndash65 2003

[6] C Hoare ldquoThe trypanosomes of mammalsrdquo Journal of SmallAnimal Practice vol 13 pp 671ndash672 1972

[7] C J Schofield ldquoOverview evolution of the triatominaerdquo in Pro-ceedings of the 2nd International Workshop on Population Gen-etics and Control of Triatominae C J Schofield and C PonceEds INDRE Tegucigalpa Honduras 1998

[8] F Rothhammer M J Allison L Nunez V Standen and BArriaza ldquoChagas disease in pre-Columbian South AmericardquoAmerican Journal of Physical Anthropology vol 68 no 4 pp495ndash498 1985

[9] J R Coura ldquoChagas disease what is known and what isneededmdasha background articlerdquoMemorias do Instituto OswaldoCruz vol 102 no 1 pp 113ndash122 2007

[10] A C Aufderheide W Salo M Madden et al ldquoA 9000-yearrecord of Chagas diseaserdquo Proceedings of the National Academyof Sciences of USA vol 101 no 7 pp 2034ndash2039 2004

[11] Y Carlier J C PDias AO LuquettiMHonteberye F Torricoand C Truyens ldquoTrypanosomiase americaine ou maladie deChagasrdquo in Encyclopedie Medico Chirurgicale Elsevier ParisFrence 2002

[12] W B Bean ldquoThe illness of Charles DarwinrdquoTheAmerican Jour-nal of Medicine vol 65 no 4 pp 572ndash574 1978

[13] F Koberle ldquo50 Years of Chagasrsquo diseaserdquoMunchener Medizinis-che Wochenschrift vol 99 pp 1193ndash1198 1957

[14] A Moncayo and M I Ortiz Yanine ldquoAn update on Chagasdisease (humanAmerican trypanosomiasis)rdquoAnnals of TropicalMedicine and Parasitology vol 100 no 8 pp 663ndash677 2006

[15] G A Schmunis ldquoEpidemiology of Chagas disease in non-ende-mic countries the role of internationalmigrationrdquoMemorias doInstituto Oswaldo Cruz vol 102 no 1 pp 75ndash85 2007

[16] G A Schmunis and Z E Yadon ldquoChagas disease a LatinAmerican health problem becoming a world health problemrdquoActa Tropica vol 115 no 1-2 pp 14ndash21 2010

[17] J R Coura and P A Vinas ldquoChagas disease a new worldwidechallengerdquo Nature vol 465 no 7301 pp S6ndashS7 2010

[18] A F Henao-Martınez D A Schwart and I V Yang ldquoChagasiccardiomyopathy from acute to chronic is this mediated byhost susceptibility factorsrdquo Transactions of the Royal Society ofTropicalMedicine andHygiene vol 106 no 9 pp 521mdash527 2012

[19] D P Neves A L Melo and O Genaro Eds ParasitologiaHumana Atheneu Sao Paulo Brazil 2005

[20] D Born R E S Acha and M Ferraz ldquoPregnancy and Chagasrsquodiseaserdquo Journal of the American College of Cardiology vol 31p 421 1998

[21] E L P Camandaroba C M Pinheiro Lima and S G AndradeldquoOral transmission of Chagas disease importance of Trypano-soma cruzi biodeme in the intragastric experimental infectionrdquoRevista do Instituto de Medicina Tropical de Sao Paulo vol 44no 2 pp 97ndash103 2002

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Microbiology

Page 8: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

8 BioMed Research International

genetic susceptibility of single nucleotide polymorphisms incytokine genes to human Chagas disease was reviewed [105]The cytokines polymorphisms associatedwithChagas diseaseare summarized in Table 2

Proinflammatory cytokines play a key role in the develop-ment of CCC Aiming to investigate the influence of theTNF polymorphisms on Chagas disease TNFA (posi-tions minus308 rs1800629 minus244 rs673 minus238 rs361525 andminus1031 rs1799964) and TNFB genotypes have been inter-rogated No significant differences were observed withthese alleles or haplotypes between patients and controls in aPeruvian population [106]TNF-308A alsowas not associatedwith CCC in Brazilian patients [107] However the sameSNP could be directly involved in the genetic susceptibilityof the chronic phase and CCC in a Mexican population[108] Another study also in Brazilian patients suggestedthat allele TNF-238A which correlates with production ofsignificantly higher levels of TNF-120572 could influence thesusceptibility to infection [109] The TNF-1031C and -308Aalleles were significantly associated with the development ofCCC whereas the TNF-1031TT and -308GG genotypes wereassociated with lower risk to develop CCC in a Colombianpopulation [110] Regarding the TNF gene microsatellite tenalleles were associated with Chagas disease in the Brazilianpopulation eight of them correlate with susceptibility(TNFa2 TNFa7 TNFa8 TNFb2 TNFb4 TNFd5 TNFd7and TNFe2) and two with protection (TNFb7 and TNFd3)against the development of the disease [111] Previously theoccurrence of the TNFa2 microsatellite was correlated withreduced survival in severe cardiomyopathy [112] Despite thecontroversial results these data suggest the involvement ofTNF in the course of Chagas disease

Clinical genetic and epidemiological studies have linkedlymphotoxin-120572 (LTA) a proinflammatory cytokine to coro-nary artery disease and myocardial infarction In BrazilianCCC patients homozygosity with respect to the LTA+80C(rs2239704) and LTA+252G (rs909253) alleles was signifi-cantly more frequent and was associated with susceptibil-ity and the haplotype LTA+80A+252A was associated withprotection against CCC Furthermore homozygosity for theLTA+80A allele correlated with the lowest levels of plasmaticTNF-120572 [113]

It appears that IL6 gene polymorphism does not con-tribute to susceptibility in the clinical manifestations ofChagas disease In a study in two independent populationsof Colombia and Peru no difference was observed for IL6-174GC (rs1800795) between Chagas disease and controls orbetween asymptomatic patients and CCC [114]

Some IL1B alleles and haplotypes have been associatedwith susceptibility to inflammatory autoimmune and infec-tious diseases The IL1B-511(rs16944) IL1F103 (rs3811058)IL1RN4 (rs419598) IL1RN 61 (rs315952) and IL-1RN 62(rs315951) polymorphisms were analysed in Chagas diseaseand IL-1RN4CC genotype was clearly associated with Tcruzi infection and CCC development [115] The IL1B+5810G(rs1143633) allele and the haplotype IL1B-31 (rs1143627)+3954(rs1143634)CT were associatedwith an increased risk of CCC[116] Therefore these studies suggest that IL1 gene clusterpolymorphisms may play a relevant role in the susceptibility

to development of CCC and that the effect of IL1B gene onchagasic cardiomyopathy predisposition is dose dependent[116]

IL-10 and INF-120574 production by T cells promotes T cruzicontrol and protects against fatal acute myocarditis [115ndash118]The SNP IL10-1082 (rs1800896) A allele which is associatedwith a lower expression of IL-10 had higher frequency inCCC Brazilian patients when compared to the asymptomaticgroup [119]However inColombian patients no differences inallele frequency and haplotype of the IL10 genewere observedin symptomatic and asymptomatic patients [120] Linkagedisequilibrium analysis on microsatellite loci suggests epis-tasis between MHC and IL-10 on Chagas disease suscep-tibilityresistance [121] The frequency of the IFNG+874AA(rs62559044) which is associated with reduced productionof INF-120574 was increased in the Colombian patients suggestingthat this SNP may be involved in susceptibility but not in theprogression of Chagas disease [122]

IL-4 is described as a prototypical anti-inflammatorycytokine It can modulate the host and parasite survivals thatdepend on a fine balance betweenTh1 responses on one handit will control parasitism and on the other hand enhanceheart inflammation throughout the course of the infection[123] In a Bolivian population SNP IL4-590 (rs2243250)T allele was associated with protection against T cruziinfection [124] although in another study only the IL4RA(IL-4 receptor-120572 rs147781) +148AA genotype showed a weakassociation with the development of CCC [120]

TGF-120573 plays a pivotal role in Chagas disease not onlyin the development of chagasic cardiomyopathy but also inmany stages of the T cruzi life cycle and survival in the hostcell environment through regulation of (i) parasite invasionof heart cells (ii) an intracellular parasite cycle (iii) inflam-mation and immune response (iv) heart fibrosis and remod-elling and (v) gap junction modulation and heart conduc-tion [125] Several SNPs in the TGFB1 gene that may affectcytokine production have been described A significant dif-ference in the distribution of the TGFB1 10 (rs1982073) T andC alleles between patients and healthy controls was observedin the Peruvian and Colombian populations TGFB1 10CCthe high producer genotype was increased in patients of bothpopulations [126]

The IL-12 family of cytokines can influence Th17 andthe production of IL-17 and INF-120574 The SNPs rs3212227 inthe 31015840UTR of the gene IL12B were investigated and IL12B31015840UTR C allele and CC genotype were significantly increasedamong CCC patients when compared to asymptomatic indi-viduals [127]

MIF (macrophage migration inhibitory factor) minus173Callele and CC genotype were related to the major risk ofChagas disease in the Colombian and Peruvian populations[128]

Some chemokines also had been associated with thedevelopment of CCC CXCL9 CC (rs10336) and CXCL10GG (rs3921) genotypes were less frequent and CCR5 CC(rs1799988) was more frequent in patients with left ven-tricular dysfunction compared with patients without thisdysfunction and may indicate that CXCL9 and CXCL10 aremaster regulators of myocardial inflammatory cell migration

BioMed Research International 9

perhaps affecting clinical progression to the life-threateningform of CCC [129] Some SNPs of CCR5 gene were associ-ated with the development of severe cardiomyopathy in anendemic area of Colombia Peru and Venezuela [130ndash132]

In the Brazilian population BAT1 (HLA-B associatedtranscript 1) C allele and CC genotype at positions 22 CGand minus348 CT were associated with risk of cardiomyopathy[133] In the same population MCP-1 (monocyte chemo-attractant protein-1) geneCCL2-2518A allele (rs1024611) andthe CCL2-2518 AA genotype correlate with susceptibility tochronic cardiomyopathy [134] BAT1 MCP-1 and LTA maybe involved in the pathogenesis of cardiac Chagas disease

Despite the controversial results these data suggest theinvolvement of cytokines in the course of Chagas diseaseThebalance between TH1TH2T regulatory cytokines has differ-ent and opposing influences on the likelihood of infectionwith T cruzi and on the clinical course of the Chagas disease

3 Concluding Remarks

Many genetic linkages and association studies have attemptedto identify genetic variations that are involved in immuno-pathogenesis of Chagas disease However causal genetic vari-ants underlying susceptibility remain unknown due to com-plexity of parasite and host Susceptibilityresistance to Cha-gas disease involves multiple genetic variants functioningjointly each with small or moderate effects Immunologicalmechanisms protect against the disease but contribute toaggression and tissue damage Genome wide associationstudies (GWAS) and next generation sequencing (NGS) atpresent lacking in Chagas disease may help identifying novelgenetic polymorphisms with genome scale associations

The impact of pathogens on host cell functions as wellas genetic markers that were significantly associated withdisease was found on schistosomiasis [135] ascariasis [136]leprosy [137] tuberculosis [138 139] malaria [140] dengue[141] hepatitis [142 143] andHIV-1 [144ndash147] In Chagas dis-ease the 2590T allele (rs2243250) polymorphism in the pro-moter region of IL4 gene is a marker for IL4 haplotypes likelyassociated with protection against T cruzi infection [124]

The identification of the specific genes influencing Tcruzi infection and Chagas disease through genome scanstechniques could offer a particular opportunity for mappinggenes of susceptibility or resistance Further studies are neces-sary to clarify the relationship between genotype and devel-opment of disease and its clinical outcomes

The characterisation of the susceptibility genes and theirvariants has important implications not only for a betterunderstanding of disease pathogenesis but also for the con-trol and development of new therapeutic strategies for infec-tious diseases

References

[1] C Chagas ldquoNova tripanozomiaze humana Estudos sobre amorfologia e o ciclo evolutivo do Schizotrypanum cruzi n genn sp Agente etiologico Agente etiologico de uma nova entidademorbida para o homemrdquoMemorias do Instituto Oswaldo Cruzvol 1 pp 159ndash218 1909

[2] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[3] L O Andrade C R S Machado E Chiari S D J Penaand A M Macedo ldquoDifferential tissue distribution of diverseclones of Trypanosoma cruzi in infected micerdquo Molecular andBiochemical Parasitology vol 100 no 2 pp 163ndash172 1999

[4] World Health Organization (2012) Chagas disease (Americantrypanosomiasis) Fact Sheet No 340

[5] L V Kirchhoff ldquoChanging epidemiology and approaches totherapy for Chagas diseaserdquo Current Infectious Disease Reportsvol 5 no 1 pp 59ndash65 2003

[6] C Hoare ldquoThe trypanosomes of mammalsrdquo Journal of SmallAnimal Practice vol 13 pp 671ndash672 1972

[7] C J Schofield ldquoOverview evolution of the triatominaerdquo in Pro-ceedings of the 2nd International Workshop on Population Gen-etics and Control of Triatominae C J Schofield and C PonceEds INDRE Tegucigalpa Honduras 1998

[8] F Rothhammer M J Allison L Nunez V Standen and BArriaza ldquoChagas disease in pre-Columbian South AmericardquoAmerican Journal of Physical Anthropology vol 68 no 4 pp495ndash498 1985

[9] J R Coura ldquoChagas disease what is known and what isneededmdasha background articlerdquoMemorias do Instituto OswaldoCruz vol 102 no 1 pp 113ndash122 2007

[10] A C Aufderheide W Salo M Madden et al ldquoA 9000-yearrecord of Chagas diseaserdquo Proceedings of the National Academyof Sciences of USA vol 101 no 7 pp 2034ndash2039 2004

[11] Y Carlier J C PDias AO LuquettiMHonteberye F Torricoand C Truyens ldquoTrypanosomiase americaine ou maladie deChagasrdquo in Encyclopedie Medico Chirurgicale Elsevier ParisFrence 2002

[12] W B Bean ldquoThe illness of Charles DarwinrdquoTheAmerican Jour-nal of Medicine vol 65 no 4 pp 572ndash574 1978

[13] F Koberle ldquo50 Years of Chagasrsquo diseaserdquoMunchener Medizinis-che Wochenschrift vol 99 pp 1193ndash1198 1957

[14] A Moncayo and M I Ortiz Yanine ldquoAn update on Chagasdisease (humanAmerican trypanosomiasis)rdquoAnnals of TropicalMedicine and Parasitology vol 100 no 8 pp 663ndash677 2006

[15] G A Schmunis ldquoEpidemiology of Chagas disease in non-ende-mic countries the role of internationalmigrationrdquoMemorias doInstituto Oswaldo Cruz vol 102 no 1 pp 75ndash85 2007

[16] G A Schmunis and Z E Yadon ldquoChagas disease a LatinAmerican health problem becoming a world health problemrdquoActa Tropica vol 115 no 1-2 pp 14ndash21 2010

[17] J R Coura and P A Vinas ldquoChagas disease a new worldwidechallengerdquo Nature vol 465 no 7301 pp S6ndashS7 2010

[18] A F Henao-Martınez D A Schwart and I V Yang ldquoChagasiccardiomyopathy from acute to chronic is this mediated byhost susceptibility factorsrdquo Transactions of the Royal Society ofTropicalMedicine andHygiene vol 106 no 9 pp 521mdash527 2012

[19] D P Neves A L Melo and O Genaro Eds ParasitologiaHumana Atheneu Sao Paulo Brazil 2005

[20] D Born R E S Acha and M Ferraz ldquoPregnancy and Chagasrsquodiseaserdquo Journal of the American College of Cardiology vol 31p 421 1998

[21] E L P Camandaroba C M Pinheiro Lima and S G AndradeldquoOral transmission of Chagas disease importance of Trypano-soma cruzi biodeme in the intragastric experimental infectionrdquoRevista do Instituto de Medicina Tropical de Sao Paulo vol 44no 2 pp 97ndash103 2002

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

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Zoology

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BioinformaticsAdvances in

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Signal TransductionJournal of

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Microbiology

Page 9: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

BioMed Research International 9

perhaps affecting clinical progression to the life-threateningform of CCC [129] Some SNPs of CCR5 gene were associ-ated with the development of severe cardiomyopathy in anendemic area of Colombia Peru and Venezuela [130ndash132]

In the Brazilian population BAT1 (HLA-B associatedtranscript 1) C allele and CC genotype at positions 22 CGand minus348 CT were associated with risk of cardiomyopathy[133] In the same population MCP-1 (monocyte chemo-attractant protein-1) geneCCL2-2518A allele (rs1024611) andthe CCL2-2518 AA genotype correlate with susceptibility tochronic cardiomyopathy [134] BAT1 MCP-1 and LTA maybe involved in the pathogenesis of cardiac Chagas disease

Despite the controversial results these data suggest theinvolvement of cytokines in the course of Chagas diseaseThebalance between TH1TH2T regulatory cytokines has differ-ent and opposing influences on the likelihood of infectionwith T cruzi and on the clinical course of the Chagas disease

3 Concluding Remarks

Many genetic linkages and association studies have attemptedto identify genetic variations that are involved in immuno-pathogenesis of Chagas disease However causal genetic vari-ants underlying susceptibility remain unknown due to com-plexity of parasite and host Susceptibilityresistance to Cha-gas disease involves multiple genetic variants functioningjointly each with small or moderate effects Immunologicalmechanisms protect against the disease but contribute toaggression and tissue damage Genome wide associationstudies (GWAS) and next generation sequencing (NGS) atpresent lacking in Chagas disease may help identifying novelgenetic polymorphisms with genome scale associations

The impact of pathogens on host cell functions as wellas genetic markers that were significantly associated withdisease was found on schistosomiasis [135] ascariasis [136]leprosy [137] tuberculosis [138 139] malaria [140] dengue[141] hepatitis [142 143] andHIV-1 [144ndash147] In Chagas dis-ease the 2590T allele (rs2243250) polymorphism in the pro-moter region of IL4 gene is a marker for IL4 haplotypes likelyassociated with protection against T cruzi infection [124]

The identification of the specific genes influencing Tcruzi infection and Chagas disease through genome scanstechniques could offer a particular opportunity for mappinggenes of susceptibility or resistance Further studies are neces-sary to clarify the relationship between genotype and devel-opment of disease and its clinical outcomes

The characterisation of the susceptibility genes and theirvariants has important implications not only for a betterunderstanding of disease pathogenesis but also for the con-trol and development of new therapeutic strategies for infec-tious diseases

References

[1] C Chagas ldquoNova tripanozomiaze humana Estudos sobre amorfologia e o ciclo evolutivo do Schizotrypanum cruzi n genn sp Agente etiologico Agente etiologico de uma nova entidademorbida para o homemrdquoMemorias do Instituto Oswaldo Cruzvol 1 pp 159ndash218 1909

[2] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[3] L O Andrade C R S Machado E Chiari S D J Penaand A M Macedo ldquoDifferential tissue distribution of diverseclones of Trypanosoma cruzi in infected micerdquo Molecular andBiochemical Parasitology vol 100 no 2 pp 163ndash172 1999

[4] World Health Organization (2012) Chagas disease (Americantrypanosomiasis) Fact Sheet No 340

[5] L V Kirchhoff ldquoChanging epidemiology and approaches totherapy for Chagas diseaserdquo Current Infectious Disease Reportsvol 5 no 1 pp 59ndash65 2003

[6] C Hoare ldquoThe trypanosomes of mammalsrdquo Journal of SmallAnimal Practice vol 13 pp 671ndash672 1972

[7] C J Schofield ldquoOverview evolution of the triatominaerdquo in Pro-ceedings of the 2nd International Workshop on Population Gen-etics and Control of Triatominae C J Schofield and C PonceEds INDRE Tegucigalpa Honduras 1998

[8] F Rothhammer M J Allison L Nunez V Standen and BArriaza ldquoChagas disease in pre-Columbian South AmericardquoAmerican Journal of Physical Anthropology vol 68 no 4 pp495ndash498 1985

[9] J R Coura ldquoChagas disease what is known and what isneededmdasha background articlerdquoMemorias do Instituto OswaldoCruz vol 102 no 1 pp 113ndash122 2007

[10] A C Aufderheide W Salo M Madden et al ldquoA 9000-yearrecord of Chagas diseaserdquo Proceedings of the National Academyof Sciences of USA vol 101 no 7 pp 2034ndash2039 2004

[11] Y Carlier J C PDias AO LuquettiMHonteberye F Torricoand C Truyens ldquoTrypanosomiase americaine ou maladie deChagasrdquo in Encyclopedie Medico Chirurgicale Elsevier ParisFrence 2002

[12] W B Bean ldquoThe illness of Charles DarwinrdquoTheAmerican Jour-nal of Medicine vol 65 no 4 pp 572ndash574 1978

[13] F Koberle ldquo50 Years of Chagasrsquo diseaserdquoMunchener Medizinis-che Wochenschrift vol 99 pp 1193ndash1198 1957

[14] A Moncayo and M I Ortiz Yanine ldquoAn update on Chagasdisease (humanAmerican trypanosomiasis)rdquoAnnals of TropicalMedicine and Parasitology vol 100 no 8 pp 663ndash677 2006

[15] G A Schmunis ldquoEpidemiology of Chagas disease in non-ende-mic countries the role of internationalmigrationrdquoMemorias doInstituto Oswaldo Cruz vol 102 no 1 pp 75ndash85 2007

[16] G A Schmunis and Z E Yadon ldquoChagas disease a LatinAmerican health problem becoming a world health problemrdquoActa Tropica vol 115 no 1-2 pp 14ndash21 2010

[17] J R Coura and P A Vinas ldquoChagas disease a new worldwidechallengerdquo Nature vol 465 no 7301 pp S6ndashS7 2010

[18] A F Henao-Martınez D A Schwart and I V Yang ldquoChagasiccardiomyopathy from acute to chronic is this mediated byhost susceptibility factorsrdquo Transactions of the Royal Society ofTropicalMedicine andHygiene vol 106 no 9 pp 521mdash527 2012

[19] D P Neves A L Melo and O Genaro Eds ParasitologiaHumana Atheneu Sao Paulo Brazil 2005

[20] D Born R E S Acha and M Ferraz ldquoPregnancy and Chagasrsquodiseaserdquo Journal of the American College of Cardiology vol 31p 421 1998

[21] E L P Camandaroba C M Pinheiro Lima and S G AndradeldquoOral transmission of Chagas disease importance of Trypano-soma cruzi biodeme in the intragastric experimental infectionrdquoRevista do Instituto de Medicina Tropical de Sao Paulo vol 44no 2 pp 97ndash103 2002

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Page 10: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

10 BioMed Research International

[22] AMMacedo and S D J Pena ldquoGenetic variability of Trypano-soma cruzi implications for the pathogenesis of Chagas dis-easerdquo Parasitology Today vol 14 no 3 pp 119ndash124 1998

[23] A Moncayo ldquoChagas disease current epidemiological irendsafter the interruption of vectorial and transfusional transmis-sion in the southern cone countriesrdquo Memorias do InstitutoOswaldo Cruz vol 98 no 5 pp 577ndash591 2003

[24] L J Silva A evolucao da doenca de Chagas no Estado de SaoPaulo Editora Hucitec Sao Paulo Brazil 1999

[25] W O Dutra and K J Gollob ldquoCurrent concepts in immunoreg-ulation and pathology of human Chagas diseaserdquo CurrentOpinion in Infectious Diseases vol 21 no 3 pp 287ndash292 2008

[26] M P Barrett R J S Burchmore A Stich et al ldquoThe trypanoso-miasesrdquoThe Lancet vol 362 no 9394 pp 1469ndash1480 2003

[27] Z Brener ldquoPathogenesis and immunopathology of chronicChagas diseaserdquo Memorias do Instituto Oswaldo Cruz vol 82pp 205ndash213 1987

[28] F Guhl C Jaramillo J C Carranza andG A Vallejo ldquoMolecu-lar characterization and diagnosis of Trypanosoma cruzi and TrangelirdquoArchives ofMedical Research vol 33 no 4 pp 362ndash3702002

[29] AMoncayo andA C Silveira ldquoCurrent epidemiological trendsfor Chagas disease in Latin America and future challengesin epidemiology surveillance and health policyrdquo Memorias doInstituto Oswaldo Cruz vol 104 no 1 pp 17ndash30 2009

[30] Y Moolani G Bukhman and P J Hotez ldquoNeglected tropicaldiseases as hidden causes of cardiovascular diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 6 article e1499 2012

[31] E S Umezawa A O Luquetti G P Levitus et al ldquoSerodiag-nosis of chronic and acute Chagasrsquo disease with Trypanosomacruzi recombinant proteins results of A Collaborative Study insix Latin American countriesrdquo Journal of Clinical Microbiologyvol 42 no 1 pp 449ndash452 2004

[32] A M Afonso M H Ebell and R L Tarleton ldquoA systematicreview of high quality diagnostic tests for Chagas diseaserdquo PLOSNeglected Tropical Diseases vol 6 no 11 article e1881 2012

[33] E Dias F S Laranja A Miranda and G Nobrega ldquoChagasrsquodisease a clinical epidemiologic and pathologic studyrdquo Circu-lation vol 14 no 6 pp 1035ndash1060 1956

[34] W O Dutra O A Martins-Filho and J R Cancado ldquoActivatedT and B lymphocytes in peripheral blood of patients withChagas diseaserdquo International Immunology vol 6 pp 499ndash5061994

[35] WO Dutra O AMartins-Filho J R Cancado et al ldquoChagasicpatients lack CD28 expression on many of their circulating Tlymphocytesrdquo Scandinavian Journal of Immunology vol 43 no1 pp 88ndash93 1996

[36] W O Dutra D G Colley J C Pinto-Dias et al ldquoSelf andnonself stimulatory molecules induce preferential expansion ofCD5+B cells or activated T cells of chagasic patients respec-tivelyrdquo Scandinavian Journal of Immunology vol 51 no 1 pp91ndash97 2000

[37] R K Clark and R E Kuhn ldquoTrypanosoma cruzi does notinduce apoptosis in murine fibroblastsrdquo Parasitology vol 118no 2 pp 167ndash175 1999

[38] R L Tarleton ldquoTrypanosoma cruzi-induced suppression of IL-2production II Evidence for a role for suppressor cellsrdquo Journalof Immunology vol 140 no 8 pp 2769ndash2773 1988

[39] D B Rocha Rodrigues M A dos Reis A Romano et al ldquoInsitu expression of regulatory cytokines by heart inflammatorycells in Chagasrsquo disease patients with heart failurerdquo Clinical

and Developmental Immunology vol 2012 Article ID 3617307 pages 2012

[40] D M Vitelli-Avelar R Sathler-Avelar R L Massara et al ldquoAreincreased frequency ofmacrophage-like and natural killer (NK)cells together with high levels of NKT and CD4+CD25high Tcells balancing activated CD8+ T cells the key to control Cha-gasrsquo diseasemorbidityrdquoClinical and Experimental Immunologyvol 145 no 1 pp 81ndash92 2006

[41] R L Tarleton M J Grusby M Postan and L H GlimcherldquoTrypanosoma cruzi infection in MHC-deficient mice furtherevidence for the role of both class I- and class II-restrictedT cellsin immune resistance and diseaserdquo International Immunologyvol 8 no 1 pp 13ndash22 1996

[42] W O Dutra C A S Menezes F N A Villani et al ldquoCellu-lar and genetic mechanisms involved in the generation of pro-tective and pathogenic immune responses in human ChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[43] D M Vitelli-Avelar R Sathler-Avelar J C P Dias et al ldquoCha-gasic patients with indeterminate clinical form of the diseasehave high frequencies of circulating CD3+CD16minusCD56+ naturalkiller T cells and CD4+CD25High regulatory T lymphocytesrdquoScandinavian Journal of Immunology vol 62 no 3 pp 297ndash3082005

[44] S G Fonseca M M Reis V Coelho et al ldquoLocally producedsurvival cytokines IL-15 and IL-7 may be associated to thepredominance of CD8+ T cells at heart lesions of humanchronic chagas disease cardiomyopathyrdquo Scandinavian Journalof Immunology vol 66 no 2-3 pp 362ndash371 2007

[45] R Correa-Oliveira J A S Gomes E M Lemos et al ldquoTherole of the immune response on the development of severe clin-ical forms of human Chagas diseaserdquo Memorias do InstitutoOswaldo Cruz vol 9 supplement 1 pp 253ndash255 1999

[46] R C Goldenberg D A Iacobas S Iacobas et al ldquoTranscrip-tomic alterations in Trypanosoma cruzi-infected cardiac myo-cytesrdquo Microbes and Infection vol 11 no 14-15 pp 1140ndash11492009

[47] C M Calvet T G Melo L R Garzoni et al ldquoCurrent under-standing of the Trypanosoma cruzi-cardiomyocyte interactionrdquoFrontiers in Immunology vol 3 p 327 2012

[48] D drsquoAvila Reis E M Lemos G C Silva et al ldquoPhenotypiccharacterization of the inflammatory cells in chagasic megaoe-sophagusrdquoTransactions of the Royal Society of TropicalMedicineand Hygienee vol 95 pp 177ndash178 2001

[49] A B Da Silveira S J Adad R Correa-Oliveira J B Furnessand D drsquoAvila Reis ldquoMorphometric study of eosinophils mastcells macrophages and fibrosis in the colon of chronic chagasicpatients with andwithoutmegacolonrdquo Parasitology vol 134 no6 pp 789ndash796 2007

[50] G M Cardoso M J Morato J A Gomes et al ldquoComparativeanalysis of cell phenotypes in different severe clinical forms ofChagasrsquo diseaserdquo Frontiers in Bioscience vol 11 no 1 pp 1158ndash1163 2006

[51] V Michailowsky K Luhrs M O Rocha D Fouts R T Gazz-inelli and J E Manning ldquoHumoral and cellular immune res-ponses toTrypanosoma cruziTrypanosoma cruzi-derived para-flagellar rod proteins in patients with Chagasrsquo diseaserdquo Infectionand Immunity vol 71 no 6 pp 3165ndash3171 2003

[52] A R Vago L O Andrade A A Leite et al ldquoGenetic character-ization of Trypanosoma cruzi directly from tissues of patientswith chronic chagas disease differential distribution of genetic

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

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BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Page 11: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

BioMed Research International 11

types into diverse organsrdquo American Journal of Pathology vol156 no 5 pp 1805ndash1809 2000

[53] W O Dutra C A S Menezes F N A Villani et al ldquoCell-ular and genetic mechanisms involved in the generation ofprotective and pathogenic immune responses in humanChagasdiseaserdquoMemorias do Instituto Oswaldo Cruz vol 104 supple-ment 1 pp 208ndash218 2009

[54] A Schriefer and EM Carvalho ldquoBiomarcadores emmedicinardquoGazeta Medica da Bahia vol 78 pp 47ndash51 2008

[55] FIOCRUZ Polimorfismos geneticos e suscetibilidade a cardio-patia Chagasica httpwwwfiocruzbrchagascgicgiluaexesysstarthtmsid=96

[56] D G Mack J J Johnson F Roberts et al ldquoHLA-class II genesmodify outcome of Toxoplasma gondii infectionrdquo InternationalJournal for Parasitology vol 29 no 9 pp 1351ndash1358 1999

[57] M T Fernandez-Mestre Z Layrisse S Montagnani et alldquoInfluence of theHLAclass II polymorphism in chronicChagasrsquodiseaserdquo Parasite Immunology vol 20 no 4 pp 197ndash203 1998

[58] I A Colorado H Acquatella F Catalioti M T Fernandez andZ Layrisse ldquoHLA class II DRB1 DQB11 DPB1 polymorphismand cardiomyopathy due to Trypanosoma cruzi chronic infec-tionrdquo Human Immunology vol 61 no 3 pp 320ndash325 2000

[59] Z Layrisse M T Fernandez S Montagnani et al ldquoHLA-Clowast03is a risk factor for cardiomyopathy in Chagas diseaserdquo HumanImmunology vol 61 no 9 pp 925ndash929 2000

[60] E Llop F Rothhammer M Acuna andW Apt ldquoHLA antigensin cardiomyopathic Chilean chagasicsrdquo American Journal ofHuman Genetics vol 43 no 5 pp 770ndash773 1988

[61] E Llop F Rothhammer M Acuna W Apt and A ArribadaldquoHLA antigens in Chagas cardiomyopathy new evidence basedon a case-control studyrdquo Revista Medica De Chile vol 119 no 6pp 633ndash636 1991

[62] GM Sierp and E D Albert ldquoAnalysis of the HLA datardquo in Pro-ceedings of the 5th Latin American HistocompatibilityWorkshopC Gorodezky G Sierp and E Albert Eds ImmunogeneticsLaboratory 1992

[63] N H Deghaide R O Dantas and E A Donadi ldquoHLA classI and II profiles of patients presenting with Chagasrsquo diseaserdquoDigestive Diseases and Sciences vol 43 no 2 pp 246ndash252 1998

[64] M M De Oliveira Dalalio J E Laguila Visentainer R AMoliterno A M Sell and M L Petzel-Erler ldquoAssociation ofHLA-DR2 with chronic chagasic cardiopathy in a population atParana Northeast region Brazilrdquo Acta Scientiarum vol 24 pp727ndash730 2002

[65] K C Fae S A Drigo E Cunha-Neto et al ldquoHLA and120573-myosinheavy chain do not influence susceptibility to Chagasrsquo diseasecardiomyopathyrdquo Microbes and Infection vol 2 no 7 pp 745ndash751 2000

[66] A Nieto Y Beraun M D Callado et al ldquoHLA haplotypes areassociated with differential susceptibility to Trypanosoma cruziinfectionrdquo Tissue Antigens vol 55 no 3 pp 195ndash198 2000

[67] DCruz-Robles P A Reyes VMMonteon-Padilla A ROrtiz-Muniz and G Vargas-Alarcon ldquoMHC class I and class II genesin mexican patients with Chagas diseaserdquoHuman Immunologyvol 65 no 1 pp 60ndash65 2004

[68] S G Borras C Diez C Cotorruelo et al ldquoHLA class IIDRB1 polymorphism in Argentinians undergoing chronic Try-panosoma cruzi infectionrdquo Annals of Clinical Biochemistry vol43 part 3 pp 214ndash216 2006

[69] S G Borrs L Racca C Cotorruelo C Biondi J Beloscar andA Racca ldquoDistribution of HLA-DRB1 alleles in argentinean

patients with chagasrsquo disease cardiomyopathyrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 268ndash275 2009

[70] F del Puerto J E Nishizawa M Kikuchi et al ldquoProtec-tive human leucocyte antigen haplotype HLA-DRB1lowast01-Blowast14against chronic Chagas disease in Boliviardquo PLoS NeglectedTropical Diseases vol 6 no 3 article e1587 2012

[71] S Bauer V Groh J Wu et al ldquoActivation of NK cells and T cellsby NKG2D a receptor for stress-inducible MICArdquo Science vol285 no 5428 pp 727ndash729 1999

[72] DM Pardoll ldquoImmunology stress NK receptors and immunesurveillancerdquo Science vol 294 no 5542 pp 534ndash536 2001

[73] A Steinle P Li D L Morris et al ldquoInteractions of humanNKG2D with its ligands MICA MICB and homologs of themouse RAE-1 protein familyrdquo Immunogenetics vol 53 no 4 pp279ndash287 2001

[74] S Bahram M Bresnahan D E Geraghty and T Spies ldquoA sec-ond lineage of mammalian major histocompatibility complexclass I genesrdquo Proceedings of the National Academy of Sciences ofthe United States of America vol 91 no 14 pp 6259ndash6263 1994

[75] H A F Stephens ldquoMICA and MICB genes can the enigma oftheir polymorphism be resolvedrdquo Trends in Immunology vol22 no 7 pp 378ndash385 2001

[76] N W Zwirner M A Fernandez-Vina and P Stastny ldquoMICA anew polymorphic HLA-related antigen is expressed mainly bykeratinocytes endothelial cells andmonocytesrdquo Immunogenet-ics vol 47 no 2 pp 139ndash148 1998

[77] N W Zwirner K Dole and P Stastny ldquoDifferential surfaceexpression of MICA by endothelial cells fibroblasts keratino-cytes and monocytesrdquo Human Immunology vol 60 no 4 pp323ndash330 1999

[78] VGrohA Steinle S Bauer andT Spies ldquoRecognition of stress-induced MHC molecules by intestinal epithelial 120574120575 T cellsrdquoScience vol 279 no 5357 pp 1737ndash1740 1998

[79] K Aida S Juarez M Kikuchi et al ldquoHLA-B35 and MICA-A5synergistically enhanced susceptibility to chagas heart diseaserdquoMHC vol 7 pp 63ndash70 2000

[80] CVilches andP Parham ldquoKIR diverse rapidly evolving recept-ors of innate and adaptive immunityrdquo Annual Review of Immu-nology vol 20 pp 217ndash251 2002

[81] R J Boyton and D M Altmann ldquoNatural killer cells killerimmunoglobulin-like receptors and human leucocyte antigenclass I in diseaserdquo Clinical and Experimental Immunology vol149 no 1 pp 1ndash8 2007

[82] S Rajagopalan and E O Long ldquoUnderstanding how combi-nations of HLA and KIR genes influence diseaserdquo Journal ofExperimental Medicine vol 201 no 7 pp 1025ndash1029 2005

[83] M P Martin X Gao J-H Lee et al ldquoEpistatic interactionbetween KIR3DS1 and HLA-B delays the progression to AIDSrdquoNature Genetics vol 31 no 4 pp 429ndash434 2002

[84] A Mendez H Granda A Meenagh et al ldquoStudy of KIR genesin tuberculosis patientsrdquo Tissue Antigens vol 68 no 5 pp 386ndash389 2006

[85] D S Franceschi P S Mazini C C Rudnick et al ldquoAssociationbetween killer-cell immunoglobulin-like receptor genotypesand leprosy in Brazilrdquo Tissue Antigens vol 72 no 5 pp 478ndash482 2008

[86] A V Marangon G F Silva C F De Moraes et al ldquoKIR genesand their human leukocyte antigen ligands in the progressionto cirrhosis in patients with chronic hepatitis CrdquoHuman Immu-nology vol 72 no 11 pp 1074ndash1078 2011

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

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BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Nucleic AcidsJournal of

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International Journal of

Microbiology

Page 12: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

12 BioMed Research International

[87] G Alter D Heckerman A Schneidewind et al ldquoHIV-1 adap-tation to NK-cell-mediated immune pressurerdquoNature vol 476no 7358 pp 96ndash100 2011

[88] L-M Yindom R Forbes P Aka et al ldquoKiller-cell immuno-globulin-like receptors andmalaria caused byPlasmodium falci-parum in the Gambiardquo Tissue Antigens vol 79 no 2 pp 104ndash113 2012

[89] C Lu X L Bai Y J Shen et al ldquoPotential implication ofactivating killer cell immunoglobulin-like receptor and HLAin onset of pulmonary tuberculosisrdquo Scandinavian Journal ofImmunology vol 76 no 5 pp 491ndash496 2012

[90] J-H Yen B E Moore T Nakajima et al ldquoMajor histocom-patibility complex class I-recognizing receptors are disease riskgenes in rheumatoid arthritisrdquo Journal of Experimental Medi-cine vol 193 no 10 pp 1159ndash1167 2001

[91] S Ramırezs-De los Santos P E Sanchez-Hernandez J FMunoz-Valle et al ldquoAssociations of killer cell immunoglobulin-like receptor genes with rheumatoid arthritisrdquoDisease Markersvol 33 no 4 pp 201ndash206 2012

[92] P Kusnierczyk ldquoKiller cell immunoglobulin-like receptor geneassociations with autoimmune and allergic diseases recurrentspontaneous abortion and neoplasmsrdquo Frontiers in Immunol-ogy 2013

[93] M Carrington and P Norman ldquoThe KIR gene clusterrdquo 2003httpwwwncbinlmnihgovbooksbookresfcgimono 003ch1d1pdf

[94] E Ashouri M H Dabbaghmanesh S Rowhanirad MBakhshayeshkaram G R Omrani and A Ghaderi ldquoActivatingKIR2DS5 receptor is a risk for thyroid cancerrdquo Human Immu-nology vol 73 no 10 pp 1017ndash1022 2012

[95] A Wisniewski R Jankowska E Passowicz-Muszynska et alldquoKIR2DL2S2 and HLA-C C1C1 genotype is associated withbetter response to treatment and prolonged survival of patientswith non-small cell lung cancer in a polish caucasian popula-tionrdquo Human Immunology vol 73 no 9 pp 927ndash31 2012

[96] D S Franceschi C A De Souza and F J Aranha ldquoImportanceof killer immunoglobulin-like receptors in allogeneic hema-topoietic stem cell transplantationrdquo Revista Brasileira de Hema-tologia e Hemoterapia vol 33 no 2 pp 126ndash130 2011

[97] E D Cox S C Hoffmann B S Dimercurio et al ldquoCytokinepolymorphic analyses indicate ethnic differences in the allelicdistribution of interleukin-2 and interleukin-6rdquo Transplanta-tion vol 72 no 4 pp 720ndash726 2001

[98] A GWilson J A Symons T L Mcdowell H O Mcdevitt andG W Duff ldquoEffects of a polymorphism in the human tumornecrosis factor 120572 promoter on transcriptional activationrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 94 no 7 pp 3195ndash3199 1997

[99] V Pravica A Asderakis C Perrey A Hajeer P J Sinnott andI V Hutchinson ldquoIn vitro production of IFN-120574 correlates withCA repeat polymorphism in the human IFN-120574 generdquo EuropeanJournal of Immunogenetics vol 26 no 1 pp 1ndash3 1999

[100] MRAwadA El-Gamel PHasletonDMTurner P J Sinnottand I V Hutchinson ldquoGenotypic variation in the transforminggrowth factor-1205731 gene Association with transforming growthfactor-1205731 production fibrotic lung disease and graft fibrosisafter lung transplantationrdquo Transplantation vol 66 no 8 pp1014ndash1020 1998

[101] D M Turner D M Williams D Sankaran M Lazarus P JSinnott and I V Hutchinson ldquoAn investigation of polymor-phism in the interleukin-10 gene promoterrdquo European Journalof Immunogenetics vol 24 no 1 pp 1ndash8 1997

[102] D S Franceschi P S Mazini C C C Rudnick et al ldquoInfluenceof TNF and IL10 gene polymorphisms in the immunopathogen-esis of leprosy in the south of Brazilrdquo International Journal ofInfectious Diseases vol 13 no 4 pp 493ndash498 2009

[103] S T Moreira D M Cardoso J E Visentainer U J V Fonzarand R A Moliterno ldquoThe possible protective role of theIL6minus174GC genotype in dengue feverrdquoThe Open Tropical Medi-cine Journal vol 1 pp 87ndash91 2008

[104] J Bidwell L Keen G Gallagher et al ldquoCytokine gene poly-morphism in human disease On-line databasesrdquo Genes andImmunity vol 1 no 1 pp 3ndash19 1999

[105] R H Vasconcelos S M Montenegro E A Azevedo Y MGomes and C N Morais ldquoGenetic susceptibility to chronicChagas disease an overview of single nucleotide polymor-phisms of cytokine genesrdquo Cytokine vol 59 no 2 pp 203ndash2082012

[106] Y Beraun A Nieto M D Collado A Gonzalez and J MartınldquoPolymorphisms at tumor necrosis factor (TNF) loci are notassociated with Chagasrsquo diseaserdquo Tissue Antigens vol 52 no 1pp 81ndash83 1998

[107] S A Drigo E Cunha-Neto B Ianni et al ldquoLack of associationof tumor necrosis factor-120572 polymorphisms with Chagas diseasein Brazilian patientsrdquo Immunology Letters vol 108 no 1 pp109ndash111 2007

[108] J M Rodrıguez-Perez D Cruz-Robles G Hernandez-Pachecoet al ldquoTumor necrosis factor-alpha promoter polymorphismin Mexican patients with Chagasrsquo diseaserdquo Immunology Lettersvol 98 no 1 pp 97ndash102 2005

[109] C W Pissetti D Correia R F De Oliveira et al ldquoGenetic andfunctional role of TNF-alpha in the development Trypanosomacruzi infectionrdquo PLoS Neglected Tropical Diseases vol 5 no 3article e976 2011

[110] L Criado O Florez J Martın and C I Gonzalez ldquoGeneticpolymorphisms in TNFATNFR2 genes and Chagas disease ina Colombian endemic populationrdquo Cytokine vol 57 no 3 pp398ndash401 2012

[111] V Campelo R O Dantas R T Simoes et al ldquoNFmicrosatellitealleles in Brazilian Chagasic patientsrdquo Digestive Diseases andSciences vol 12 pp 3334ndash3349 2007

[112] S A Drigo E Cunha-Neto B Ianni et al ldquoTNF gene polymor-phisms are associated with reduced survival in severe Chagasrsquodisease cardiomyopathy patientsrdquo Microbes and Infection vol8 no 3 pp 598ndash603 2006

[113] R Ramasawmy K C Fae E Cunha-Neto et al ldquoPolymor-phisms in the gene for lymphotoxin-120572 predispose to chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 196no 12 pp 1836ndash1843 2007

[114] O A Torres J E Calzada Y Beraun et al ldquoLack of associationbetween IL-6 -174GC gene polymorphism andChagas diseaserdquoTissue Antigens vol 76 no 2 pp 131ndash134 2010

[115] D Cruz-Robles J P Chavez-Gonzalez M M Cavazos-QueroO Perez-Mendez P A Reyes and G Vargas-Alarcon ldquoAsso-ciation between IL-1B and IL-1RN gene polymorphisms andChagasrsquo disease development susceptibilityrdquo ImmunologicalInvestigations vol 38 no 3-4 pp 231ndash239 2009

[116] O Florez G Zafra C Morillo J Martın and C I GonzalezldquoInterleukin-1 gene cluster polymorphism in Chagas disease ina Colombian Case-Control StudyrdquoHuman Immunology vol 67no 9 pp 741ndash748 2006

[117] D A DrsquoAvila P M M Guedes A M Castro E D GontijoE Chiari and L M C Galvao ldquoImmunological imbalance

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Page 13: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

BioMed Research International 13

between IFN-120574 and IL-10 levels in the sera of patients with thecardiac form of Chagas diseaserdquoMemorias do Instituto OswaldoCruz vol 104 no 1 pp 100ndash105 2009

[118] E Roffe A G Rothfuchs H C Santiago et al ldquoIL-10 limitsparasite burden and protects against fatal myocarditis in amousemodel ofTrypanosoma cruzi infectionrdquo Journal of Immu-nology vol 188 no 2 pp 649ndash660 2012

[119] G C Costa M O Costa Rocha P RMoreira et al ldquoFunctionalIL-10 gene polymorphism is associated with Chagas diseasecardiomyopathyrdquo Journal of Infectious Diseases vol 199 no 3pp 451ndash454 2009

[120] O Florez J Martın C I Gonzalez et al ldquoInterleukin 4 inter-leukin 4 receptor-120572 and interleukin 10 gene polymorphisms inChagas diseaserdquoParasite Immunology vol 33 no 9 pp 506ndash5112011

[121] M Moreno E L Silva L E Ramırez L G Palacio D Riveraand M Arcos-Burgos ldquoChagasrsquo disease susceptibilityresist-ance linkage disequilibrium analysis suggest epistasis betweenmajor histocompatibility complex and interleukin-10rdquo TissueAntigens vol 64 no 1 pp 18ndash24 2004

[122] O A Torres J E Calzada Y Beraun et al ldquoRole of the IFNG+874TA polymorphism in Chagas disease in a Colombianpopulationrdquo Infection Genetics and Evolution vol 10 no 5 pp682ndash685 2010

[123] M B P Soares K N Silva-Mota R S Lima M C BellintaniL Pontes-de-Carvalho and R Ribeiro-dos-Santos ldquoModula-tion of chagasic cardiomyopathy by interleukin-4 dissociationbetween inflammation and tissue parasitismrdquoAmerican Journalof Pathology vol 159 no 2 pp 703ndash709 2001

[124] L E Alvarado Arnez E N Venegas C Ober and E EThompson ldquoSequence variation in the IL4 gene and resistanceto Trypanosoma cruzi infection in Boliviansrdquo Journal of Allergyand Clinical Immunology vol 127 no 1 pp 279ndash282 2011

[125] T C Araujo-Jorge M C Waghabi S Bailly et al ldquoThe TGF-120573 pathway as an emerging target for Chagas disease therapyrdquoClinical Pharmacology amp Therapeutics vol 92 no 5 pp 613ndash621 2012

[126] J E Calzada Y Beraun C I Gonzalez and J Martın ldquoTrans-forming growth factor beta 1 (TGF1205731) gene polymorphismsand Chagas disease susceptibility in Peruvian and Colombianpatientsrdquo Cytokine vol 45 no 3 pp 149ndash153 2009

[127] G Zafra C Morillo J Martın A Gonzalez and C I GonzalezldquoPolymorphism in the 31015840 UTR of the IL12B gene is associatedwith Chagasrsquo disease cardiomyopathyrdquo Microbes and Infectionvol 9 no 9 pp 1049ndash1052 2007

[128] O A Torres J E Calzada Y Beraun et al ldquoAssociation ofthe macrophage migration inhibitory factor -173GC polymor-phism with Chagas diseaserdquoHuman Immunology vol 70 no 7pp 543ndash546 2009

[129] L G Nogueira R H B Santos B M Ianni et al ldquoMyocardialchemokine expression and intensity of myocarditis in Chagascardiomyopathy are controlled by polymorphisms in CXCL9and CXCL10rdquo PLOS Neglected Tropical Diseases vol 6 no 10article e1867 2012

[130] O Florez J Javier Martın and C I Gonzalez ldquoGenetic variantsin the chemokines and chemokine receptors in Chagas diseaserdquoHuman Immunology vol 73 pp 852ndash858 2012

[131] J E Calzada A Nieto Y Beraun and J Martın ldquoChemokinereceptor CCR5 polymorphisms and Chagasrsquo disease cardiomy-opathyrdquo Tissue Antigens vol 58 no 3 pp 154ndash158 2001

[132] M T Fernandez-Mestre S Montagnani and Z Layrisse ldquoIs theCCR5-59029-GG genotype a protective factor for cardiomy-opathy in Chagas diseaserdquo Human Immunology vol 65 no 7pp 725ndash728 2004

[133] R Ramasawmy E Cunha-Neto K C Fae et al ldquoThemonocytechemoattractant protein-1 gene polymorphism is associatedwith cardiomyopathy in human Chagas diseaserdquo Clinical Infec-tious Diseases vol 43 no 3 pp 305ndash311 2006

[134] R Ramasawmy E Cunha-Neto K C Fae et al ldquoBAT1 aputative anti-inflammatory gene is associated with chronicchagas cardiomyopathyrdquo Journal of Infectious Diseases vol 193no 10 pp 1394ndash1399 2006

[135] S Williams-Blangero J L Vandeberg J Subedi et al ldquoGeneson chromosomes 1 and 13 have significant effects on Ascarisinfectionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 99 no 8 pp 5533ndash5538 2002

[136] S Marquet L Abel D Hillaire et al ldquoGenetic localization ofa locus controlling the intensity of infection by Schistosomamansoni on chromosome 5q31-q33rdquoNature Genetics vol 14 no2 pp 181ndash184 1996

[137] F R Zhang W Huang S M Chen et al ldquoGenomewide asso-ciation study of leprosyrdquoThe New England Journal of Medicinevol 361 no 27 pp 2609ndash2618 2009

[138] TThye F O Vannberg S H Wong et al ldquoGenome-wide asso-ciation analyses identifies a susceptibility locus for tuberculosison chromosome 18q112rdquoNatureGenetics vol 42 no 9 pp 739ndash741 2010

[139] S Mahasirimongkol H Yanai T Mushiroda et al ldquoGenome-wide association studies of tuberculosis in Asians identifydistinct at-risk locus for young tuberculosisrdquo Journal of HumanGenetics vol 57 no 6 pp 363ndash367 2012

[140] M Jallow Y Y Teo K S Small et al ldquoGenome-wide andfine-resolution association analysis of malaria in West AfricardquoNature Genetics vol 41 no 6 pp 657ndash665 2009

[141] C C Khor T N B Chau J Pang et al ldquoGenome-wide asso-ciation study identifies susceptibility loci for dengue shock syn-drome at MICB and PLCE1rdquoNature Genetics vol 43 no 11 pp1139ndash1141 2011

[142] A Rauch Z Kutalik P Descombes et al ldquoGenetic variationin IL28B Is associated with chronic hepatitis C and treatmentfailure a genome-wide association studyrdquoGastroenterology vol138 no 4 pp 1338ndash1345 2010

[143] Y Kamatani S Wattanapokayakit H Ochi et al ldquoA genome-wide association study identifies variants in the HLA-DP locusassociated with chronic hepatitis B in Asiansrdquo Nature Geneticsvol 41 no 5 pp 591ndash595 2009

[144] J Fellay K V Shianna D Ge et al ldquoA whole-genome associ-ation study of major determinants for host control of HIV-1rdquoScience vol 317 no 5840 pp 944ndash947 2007

[145] J Fellay D Ge K V Shianna et al ldquoCommon genetic variationand the control of HIV-1 in humansrdquo PLOS Genetics vol 5 no12 article e1000791 2009

[146] K Pelak D B Goldstein andNMWalley ldquoHost determinantsof HIV-1 control in African Americansrdquo Journal of InfectiousDiseases vol 201 no 8 pp 1141ndash1149 2010

[147] S Limou S Le Clerc C Coulonges et al ldquoGenomewide asso-ciation study of an AIDS-nonprogression cohort emphasizesthe role played by HLA genes (ANRS genomewide associationstudy 02)rdquo Journal of Infectious Diseases vol 199 no 3 pp 419ndash426 2009

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology

Page 14: Review Article Genetic Susceptibility to Chagas Disease ...downloads.hindawi.com/journals/bmri/2013/284729.pdf · Review Article Genetic Susceptibility to Chagas Disease: An Overview

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Molecular Biology International

GenomicsInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioinformaticsAdvances in

Marine BiologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Signal TransductionJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Evolutionary BiologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Genetics Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Enzyme Research

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

Microbiology