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Periodontology 2000. Vol. 14. 1997,202-215Printed in Denmark . All ngh& reserved C o p y r i g h t 8 Munks gaar d 1997PERIODONTOLOGY 2000ISSN 0906-6713

Genetic factorsin thepathogenesis of periodontitisT H O M A S . H A R T& KENNETHS . KORNMAN

Periodontal disease may be regarded as a range ofdifferent diseases for which certain individuals are atrelatively high risk (44). In high-risk patient groups,host factors appear to play an important role in sus-ceptibility to periodontitis, and this risk may bepartly under genetic control.

Much of the literature about genetic diseases in-volves major genetic disorders in which the geneticfactor is sufficient by itself to cause the disease.These conditions are usually single-gene diseases,such as achondroplasia, Tay-Sachs disease and fam-ilial hypercholesterolemia, or chromosome abnor-malities involving an altered number or an alteredstructure of chromosomes, such as Down syndrome(trisomy 21). In both single-gene diseases and chro-mosomal abnormalities the disease may be clinicallyevident in childhood or produces some pathologicalmanifestations in childhood. Many common dis-eases, such as heart disease and osteoporosis, havesubstantial genetic components but they behave dif-ferently from single-gene or chromosomal disorders.These multifactorial diseases usually involve com-plex interactions among multiple genes and environ-mental factors. In muitifactorial diseases the gen-etics are not, by themselves, sufficient for the dis-ease, and the clinical signs and symptoms are notusually evident until adulthood. Disease traits thatmay be measured on a continuous scale, such asblood pressure or bone density, are often multifacto-rial because they are the cumulative function ofmultiple genetic and environmental influences.

Considerable evidence suggests that there is somegenetic basis for early-onset forms of periodontaldisease (10, 41 , 103), consistent with single-gene in-heritance. Support for genetic susceptibility for themore common forms of adult periodontitis is alsoincreasing and suggests a multifactorial disease pat-tern. The results of twin studies clearly indicate thata significant part of the variance in clinical andradiographic measures of adult periodontitis may beexplained by genetic factors (20, 73, 74).

Genetically determined variance in human im-mune responses to various bacterial infections hasbeen clearly identified (9, 52, 65,69,87),and a num-ber of these, or similar factors, may be importantdeterminants for periodontal disease susceptibilityand disease expression (Tables 1, 2 ) . This chapteroutlines the search for genetic risk factors for early-onset as well as adult-onset periodontal diseases andpresents this information in the context of the para-digm shift that has occurred in our understanding ofperiodontal diseases.

A paradigm shiftPeriodontal diseases are a heterogeneous group ofdiseases that affect more than 50 million people inthe United States and hundreds of millions aroundthe world. A unifying theme in models of peri-odontal pathogenesis is the requisite role of mi-crobial agents (77, 109). Epidemiological and mol-ecular studies of the oral microbial flora suggest,however, that although microbial factors are re-quired for disease, they alone do not predict thepresence or severity of periodontitis. In recent yearselements of host susceptibility, such as immune re-sponse and systemic disease state, and other nonmi-crobial environmental factors, such as smoking,have been shown to be important contributors to thedisease expression (35, 791. The most current multi-variate models of periodontitis that incorporate mi-crobial factors have correlation coefficients in the0.3-0.4 range for the presence, absence or level ofspecific microbes believed to be periodontal patho-gens (6, 18, 124). These results suggest that less than20% of variability in periodontal disease expressioncan be explained by the levels of specific microbes.Statistical models of multifactorial diseases are com-plicated, because multiple patterns of pathogenicmechanisms may lead to a single clinical diseasepattern. For example, in recent studies the statistical

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Genetic factors in the pathogenesis of periodontitis

Table 1. Genetic loci associated with host immune response to microbial infectionGene locus

CD32 receptor(receptor for Fcfragment of IgG)CD16 (receptor forFc fragment of IgG)

~~

MIM Genemapno. locus Comments146790 lq21-q23 AUelic variants of the Fc-gamma receptor confer distinct phagocyticcapacities, providing a mechanism for heritable susceptibility to microbial

infections.Fc receptor I11 is encoded by 2 separate genes, one for the neutrophilreceptor (CD16) and another for the transmembrane receptors onmacrophages. Allelic variants of CD16 may affect susceptibility torecurrent viral infections.146740 lq23

Blood group P system 111400 6(P globoside) Many bacterial infections require that the bacteria can adhere toepithelial cells of the host. Receptors on human epithelial cells and redblood cells are ycosphingolipids related to human P blood groupsystem. The P1f ood group phenotype is associated with pyelonephritis.Lewis blood group Women with recurrent urinary tract infections have an increasedfrequency of the Lewis blood group nonsecretor (Le(a+b-] and recessive(Le(a-b-1 phenotype.Lipopolysaccharide- 151990 2Oq11.23-ql2 Lipopolysaccharide-bindingprotein is synthesized during the acutebinding protein phase of infection and is thought to function as a carrier forlipopolysaccharide and to control lipopolysaccharide-dependentmonocyte responses.Prostaglandin 600262 1q25.2-25.3 Prostaglandin endoperoxide synthase has a major role in regulatingendoperoxide synthase2 (also referred to ascyclooxygenase 2)

prostaglandin synthesis. h o isoforms are known, prostaglandinendoperoxide synthase 1 and 2. Lipopolysaccharideprovokes a dramaticinduction of prostaglandin endoperoxide synthase 2 messenger RNA innormal peripheral blood monocytes; in contrast, prostaglandinendoperoxide svnthase 1 shows minimal induction.~~Prostaglandinendoperoxide synthase1 (also referred to ascyclooxygenase 1)

176805 9q32-33.3 Prostaglandin endoperoxidase synthase is the key enzyme inprostaglandin biosynthesis.The two isozymes differ in their regulation ofexpression and their tissue distribution. prostaglandin endoperoxidesynthase 1 is involved in cell-cell signaling and maintaining tissuehomeostasis.Lysozyme 153450 12 Catalyzes hydrolysis of bacterial cell walls. Inherited lysozyme deficiencyhas been identified in animals with increased susceptibility toinfections. Different tissue-specific isozymes have been identified.'lkmor necrosis 191160 6p21.3 At lo w levels, tumornecrosis factor a protects against infectious insultfactor a by enhancing antigen presentation and by upregulating cell surface levels

of adhesion molecules and IgG receptors and complement. Geneticpolymorphisms have been identified in the TNFa gene promoter region.Regulatory polymorphisms of cytokine genes can affect the outcome ofinfection. The maintenance of certain TNFa alleles (such as TNF2) incertain populations impIies some biological advantage.panoply of host reactions known collectively as the acute-phase response.Several genetic polymorphisms have been described in genes of theinterleukin-1 cluster, and several of these polymorphisms have beenassociated with an increased severitv of inflammatorv disease.

Interleukin-lp 147720 2q13-q21 Interleukin-1 s produced mainly by blood monocytes and mediates the

~~MIM no. efers to the catalogue number ascribed in McKusick's Mendelian inheritance in man catalogue.

contribution of smoking to disease was similar tothat attributed to bacteria (79).Although these ob-servations underscore the importance of incorporat-ing host and other environmental factors in modelsof periodontal disease, the interpretation of suchanalyses is complex. Many past attempts to clarifythe relative contributions of various factors, such asgenetics, in the etiology of periodontitis did not dif-ferentiate the diverse roles different factors may playin pathogenesis. For example, initiating factors, suchas specific bacteria, may not appear strongly associ-ated with the magnitude of tissue destruction if arange of disease modifiers, such as smoking, are

present. Similarly, one disease severity determinantsuch as smoking (104)may mask the relative import-ance of other disease modifiers that may be import-ant in the absence of smoking (52, 93).

A major part of the shift in thinking, therefore, in-volves the recognition that bacteria are essential forthe initiation and progression of periodontitis, butother factors, such as smoking and genetics, appearto strongly influence severity of the disease that re-sults. New models of how these factors relate to dis-ease may be necessary in both research and clinicaltherapy situations.

Refining the concepts concerning the causes of

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Table 2. Disease conditions attributed to genetically transmitted alterations in immune response tomicrobial infectionMIM GenemapDisease no. locus Inheritance Comments

Leukocyte adhesion 116920 21q22.3 Autosomal recessive Disorder of neutrophil function resulting fromdeficiency type 1 deficiency of beta-2 integrin subunit of the leukocytecell adhesion molecule.Familial disseminated 209950 2q33-37 Autosomal Bcg gene is expressed in 2 allelic forms, a dominantatypical mycobacterialinfection allele; autosomal macrophage function.dominant resistance resistance allele and parasitic infection, and affectsrecessivesusceptibility alleleChBdiak-Higashi 214500 1q42.1-42.2 Autosomal recessive Clinical findings include neutropenia and abnormalsvndrome susceptibility o infection.Chronic 306400 Xp21.1 X-linked recessive In this disorder, neutrophils can phagocytosegranulomatousdisease bacteria but cannot kill them in the phagocyticvacuoles. The cause of the killing defect is an inabilityto increase the cells respiration and consequentfailure to deliver activated oxygen into the phagocytlcvacuole.Specific granule 245480 3q21-q23 Autosomal recessive Lactoferrinhas strong bacteriostatic properties anddeficiency (alsocalledlactoferrin-deficientneutrophils)

can deprive bacteria of the iron essential for growth.It may also protect cells from free radical damage.Patientswith specific granule deficiency have normalneutrophil counts, but have a tissue Ineutrophil)-specific absence of lactofemn secondary to anabnormality of RNA production, possibly due to adefective granule-packaging gene.catalyzes production of intermediates withmicrobicidal activity against a wide range ofmicrobes. Exaggerated superoxide production; severalallelic variants have been identified.

Myeloperoxide 254600 17q12-21 Autosomal recessive Absence of myeloperoxidase, a dimeric protein thatdeficiency

Localized juvenile 170650 4qll-113 Autosomal A major gene locus has been mapped toDeriodontitis dominant chromosome 4q. The genetic defect is unknown.MI M no refers to the catalogue number ascribed in McKusicKs Mendelian inheritance in m an catalogue.

disease is further complicated because periodontaldiseases have many of the characteristics of complexdiseases that make genetic studies difficult. Thesecharacteristics include difficulty in measuring andclassifying disease phenotypes, the temporal natureof disease and the complex interaction of host, gen-etic, microbial and other environmental factors (91).However, the advent of current research tools makesit possible to begin to identify and partition specificelements of susceptibility and to incorporate theseinto periodontal disease models. Identification andcharacterization of specific risk elements may pro-vide diagnostic and prognostic biomarkers appli-cable for estimating risk in individuals.

Although familial aggregation of periodontal dis-eases has long been recognized (421, until recently ithas been most expeditious to concentrate on en-vironmental factors that contribute to the disease(42, 82).A primary reason is that the tools needed todissect out genetic components of disease suscepti-bility for complex muitifactorial diseases such asperiodontitis were simply not available Research

into genetic components of periodontal diseases wasunable to provide practical information to permittranslation of genetic findings into the clinical deliv-ery of treatment. Ironically, the prevailing view ofperiodontitis as a ubiquitous finding in humanpopulations reduced emphasis on genetic import-ance in the disease process. Interindividual differ-ences in disease susceptibility appeared less import-ant in traditional paradigms of periodontal disease.However, as oral hygiene habits improved and classi-fication of periodontitis evolved, including measuresof the destructive process, disease prevalence esti-mates decreased. Not everyone appeared equallysusceptible to the disease process. A few classic ob-servations have demonstrated the apparent vari-ability in host susceptibility to a bacterial challenge.Lindhe et al. (58) in an experimental periodontitisstudy in dogs noted that, with long-term plaque ac-cumulation and gingivitis development, some of thedogs developed no to only minimal loss of attach-ment. Similarly, in tea plantation workers in Sri Lan-ka (61),with no oral hygiene or professional dental

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Genetic factors in the pathogenesis ofperiodontitiscare, three distinct patterns of periodontitis wereevident, including some individuals who developedonly minimal disease (11% of the population) andsome who developed severe generalized peri-odontitis (8% of the population). As a result, sometraditional concepts of the role of etiological factorsin periodontal diseases have changed. Perhaps themost significant aspect of this paradigm shift hasbeen the realization of the centrality of host suscep-tibility as a modifier of the clinical outcomes of thebacterial challenge (39, 78, 79, 110). This change inperspective and the introduction of new statisticaland molecular biological research techniques haveled to a renewed emphasis on the search for geneticcomponents for susceptibility to periodontitis.

Evidence for genetic susceptibilityto periodontal diseasesEvidence for a genetic influence on periodontitiscomes from multiple sources including familial ag-gregation and formal genetic studies of early-onsetforms of periodontitis, the association of peri-odontitiswth certain Mendelian inherited diseases,and twin studies of adult periodontitis. The specificelements of support from these lines of evidencehave been presented in several recent reviews (39,75, 76) . In addition, Hassell & Harris (42) have pro-vided an enlightening review of earlier twin studies,primarily from the German literature, suggestingthat a significant component of the risk for peri-odontitis is genetic. Identification of genetic factorsthat control the immune response to various mi-crobial infections in both the murine and humanmodels has increased the emphasis on geneticallydetermined host responses (4, 65, 66). Additionalsupport for a genetic contribution for periodontitisemerged recently from identification of certain gen-etic polymorphisms that correlate with immune re-sponse phenotypes found in certain groups of peri-odontitis patients (52, 78).

Much of the support for a genetic role in peri-odontitis has come from early-onset periodontitis,which has been studied extensively by the classicgenetic techniques of segregation analysis and link-age analysis. These data are outlined below.

Familial aggregation and early-onset periodontitisChronic diseases that have high population frequen-cies tend to aggregate in families. This familial aggre-

gation is often due to environmental, socioeconomicas well as heritable factors. The genetic mechanismfor commonly occurring chronic disease is generallyacknowledged to have a complex etiology (54). Theidea that genetic susceptibility may be important forperiodontal disease expression is not new. Familialaggregation has long been suspected for early-onsetforms of disease and, to a lesser extent, for adultperiodontal disease (42). Numerous studies have re-ported familial aggregation for early-onset peri-odontitis (5, 7, 10, 11, 15, 19, 28, 29, 45, 51, 62, 67,72, 81, 100, 112, 115). The observed familial aggre-gation of early-onset periodontitis is certainly con-sistent wth a heritable component of the disease.However, common familial environment and fam-ilial transmission of oral microbes may also affectsuch a disease pattern (1, 88). More formal geneticstudies of the familial aggregation of early-onsetperiodontitis have supported genetic transmission ofthe trait (10, 67, 72, 100).

To determine whether the observed familial aggre-gation for early-onset periodontitis supports genetictransmission of the disease, segregation analyseswere performed. Genetic segregation analysis is amethod of assessing support for various hypo-thesized inheritance patterns for a trait of interest,based on the observed pattern of transmission of thetrait in families being studied. Segregation analysisonly identifies which of the tested models for trans-mission of the trait is most consistent with the ob-served data. Genetic segregation analysis dependson accurate input of clinical findings and familial re-lationships and on genetic assumptions of the analy-sis. If the data input into segregation analysis are in-accurate, the outcome of the analysis will reflect this.

Earlier studies of early-onset periodontitis werehampered by clinical ascertainment bias that re-sulted in an over-representation of affected femalesand by difficulty in diagnosing early-onset peri-odontitis, particularly in older individuals (36, 101).In addition, some earlier studies did not evaluate alllikely models of inheritance for early-onset peri-odontitis, and the conclusions of the studies there-fore reflected weakness in study design (37, 67). Al-though all segregation analyses for early-onset peri-odontitis have supported a genetic transmission ofthe trait (62, 721, their conclusions differed in termsof the pattern of inheritance, primarily for reasonsdescribed above. When additional genetic modelsare evaluated, and ascertainment bias is carefullyconsidered, these earlier data are actually supportiveof autosomal dominant inheritance for early-onsetperiodontitis (37) .

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Hart & KornmanTo date, the largest and most comprehensive seg-

regation analysis for early-onset periodontitis hasbeen performed by Marazita et al. (67). Their resultsof over 100 families in the United States segregatingfor early-onset periodontitis are most supportive ofan autosomal dominant transmission for early-onsetperiodontitis. The different reported modes of in-heritance for early-onset periodontitis have causedsome confusion. Given the evidence for probablegenetic heterogeneity for early-onset periodontitisbased on clinical, immunological and genetic link-age studies, there are probably more than a few gen-etic forms of early-onset periodontitis. Although allgenetic segregation analyses of early-onset peri-odontitis support a Mendelian pattern of trans-mission, each different form of early-onset peri-odontitis may be genetically transmitted in a differ-ent Mendelian manner. The preponderance ofevidence supports autosomal dominant inheritanceof early-onset periodontitis in populations in theUnited States, and autosomal recessive inheritancein certain northern European and South Americanpopulations (63, 67, 100). However, given the diffi-culties in diagnostic determination and the evidencefor genetic heterogeneity for early-onset peri-odontitis (10, 38, 120), there may well be forms ofearly-onset periodontitis transmitted in other Mend-elian fashions.

Genetic linkage analysis and early-onsetperiodontitisGenetic linkage is a method of determining the chro-mosomal location of a gene of major effect for a trait.For reviews of genetic linkage studies for early-onsetperiodontitis, see Hart et al. (38 , 39). Identificationof genetic linkage can confirm that genetic factorsare involved in determining a trait. Boughman et al.(10) reported genetic linkage for localized juvenileperiodontitis segregating as an autosomal dominanttrait in an extended kindred from the Brandywinepopulation from eastern Maryland. They localized amajor gene for localized juvenile periodontitis to thevicinity of the vitamin D-binding protein onchromosome 4q. Subsequent linkage studies per-formed for 19African-American and Caucasian fam-ilies did not confirm the initial linkage localizationreported on chromosome 4 and may be consistentwith genetic heterogeneity for early-onset peri-odontitis (38) . Preliminary results from the largestearly-onset periodontitis linkage studies performedto date were reported recently by Wang et al. (120).They also did not find evidence of early-onset peri-

odontitis linkage to the chromosome 4q region.Their results for linkage studies for more than 100families segregating for early-onset periodontitissuggest genetic linkage for the human leukocyteantigen (HLA) region of chromosome 6 and chromo-some 9q32-33 (120). These results support geneticheterogeneity for early-onset periodontitis.

Once a physical region of a specific chromosomehas been associated with disease one may investi-gate specific genes in that region that are likely to beinvolved in the biology of the disease and thereforeare candidates for further study. Candidate genesin the chromosome 9q32-33 region include the genefor prostaglandin endoperoxide synthase 1 (also re-ferred to as cyclooxygenase 1).Prostaglandin endop-eroxide synthase 1 is the key enzyme in constitutiveprostaglandin biosynthesis, whereas prostaglandinendoperoxide synthase 2 is the inducible form pri-marily involved in the inflammatory response. Thechromosome 6 HLA region is known to containmany genes involved in immune response in boththe murine system and humans (71). The tumor ne-crosis factor a gene maps to this region, and recentlyidentified genetic polymorphisms in the 5 egula-tory region of this gene have been shown to be in-volved in the response to an infectious challenge (24,70), and may therefore be important in some formsof periodontitis. In addition, other HLA region as-sociations have been reported previously for early-onset periodontitis (106).

Genetic susceptibility to microbialinfectionsInherited defects in specific components of the im-mune system have started to provide many clues tothe immune mechanisms underlying resistance tomicrobial infection (57). General studies of animalmodels and specific studies of the murine modelhave proved very valuable in this regard (66). In ad-dition, a few fascinating observations in humanshave provided new perspectives on how genetic vari-ants in otherwise healthy individuals may predis-pose them to more severe sequelae of microbial in-fections, and these findings may provide relevantmodels for some forms of periodontitis.

Levin et al. (57) identified 6 children, includingfour from one village in Malta, with disseminatedatypical mycobacterial infection that persisted aftertherapy with multiple antimicrobial agents, althoughthey had no known immunodeficiency. These,

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Genetic factors in th e pathogenesis of periodontitischildren, and their unaffected parents, were shownto have decreased mononuclear cell production ofinterferon y and decreased monocyte production oftumor necrosis factor a, s compared with controls.In a second example, a polymorphism in the pro-moter region of the tumor necrosis factor a gene hasbeen associated with increased production of tumornecrosis factor a(21).For children infected with ma-laria, the presence of allele 2 at the tumor necrosisfactor a polymorphism was shown to convey an in-creased risk for cerebral involvement and death (70).Finally, recent studies (22, 59, 96) have highlightedthe role of genetics in the susceptibility to infectiousdiseases by demonstrating a remarkable resistanceto H N nfection in individuals with an unusual gen-etic variant in the chemokine receptor CCR5. Theseobservations and studies showing that stable im-mune phenotypic characteristics such as antibodytiter, monocyte function and cytokine productionmay result from specific genetic polymorphisms,have begun to fuel the search or genes importantin susceptibility and resistance to various microbialinfections, including periodontitis.

Candidate genes important inperiodontitis (Fig. 1)In humans, studies of inherited variations in the im-mune system are necessarily complex, and the ob-served phenotype is usuaUy the result of multiplegenetic and environmental influences. This may beespecially true for host defenses against gram-nega-tive bacteria and lipopolysaccharides, in whichmany cellular and molecular factors are involved. Itis likely that genetic polymorphisms exist for manyof these immunoinflammatory factors (57, 65).

Several immune response traits have been associ-ated with clinical forms of periodontitis, and forsome of these factors the underlying genetic deter-minants are known. Although it is unlikely that poly-morphisms in all of these genetic determinants im-part differential susceptibility to periodontal disease,it is reasonable to expect that multiple genes will befound to be important and that knowledge of thesemay permit determination of individual susceptibil-ity. The key will be to identify the genetic factors thatare important enough to impart significant clinicalrisk. In general, a gene may be considered as a can-didate for a causative or modifymg role in peri-odontitis if the physiological processes determinedby the gene have been associated with the presenceor severity of disease.

Immune regulation of immunoglobulin G2production

The serum immunoglobulin response to specific mi-crobes is an important determinant in limiting andcontrolling microbial infection. The various im-munoglobulin subclasses are known to have some-what different functional roles in the host defensesystem. Selective immunoglobulin G (IgG) subclassdeficiencies are frequently found in associationwithrecurrent infections in childhood, and IgG2 de-ficiency in particular has been associated with recur-rent infections with encapsulated bacteria such asHaemophilus influenme and Streptococcus pneu-moniue (12, 53, 80). The association of decreasedserum immunoglobulin levels, particularly of theIgG2 subclass, with poorer outcome for a number ofdifferent microbial challenges, is consistent with thehypothesis that these responses contribute to pro-tection (23, 26, 118).

IgG2 antibodies, the primary immunoglobulinsubclass that reacts with bacterial carbohydrates andlipopolysaccharides, have been reported to be thedominant immunoglobulin in both early-onset peri-odontitis and adult periodontitis (43, 90, 103, 125,126). Serum IgG2 levels in localized juvenile peri-odontitis cases are higher than serum levels of gen-eralized juvenile periodontitis cases and age-matched controls with no disease (641, which sup-ports the concept that a robust serum antibody re-sponse is associated with protection in juvenile peri-odontitis cases (34).It is of interest that levels of IgG2among African-Americans are higher than thoseamong Caucasians regardless of disease status (64).

A number of different biological mechanisms maybe involved in IgG2 variations, suggesting possiblegenetic and environmental (such as smoking)heterogeneity. For example, IgG subclasses arestrongly influenced by cytokines and may reflectgenetic variations in cytokines as well as intrinsicvariations in the B-cell populations (48).%n studies suggest that even monozygotic twinspossess and respond with different clones, indicatingthat the V-region genes, which determine the finalspecificity of B cells, either differ from the originalgermline V-region genes, owing to hypermutationsor junctional diversity, or the rearranged germlinegenes occur randomly, although highly restricted(49).

The IgG molecules carry genetically determinedvariations in the gamma heavy chains, termed Gmallotypes, and kappa light chains, termed Km allo-types. There are several Gm allotypes for IgGl and

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Fig. 1. Genetic factors in periodontitis and their potential are no current data associating a specific genetic markerbiological influence. Shown in red are candidate genetic with disease. EOP: early-onset periodontitis; LAD: leuko-factors for which there are current data to support a role cyte adhesion deficiency; PMNs: polymorphonuclearin periodontitis. Shown in yellow are candidate genetic lymphocytes; PGHS prostaglandin endoperoxide syn-factors for which there are data to support a role for the thase (alsoreferred to as cyclooxygenase).biochemical factors in periodontitis, but for which there

IgG3, but currently the only allotype identified forIgG2 is G2m(23),also referred to as G2m(n). The Gmallotype genes, or genes in linkage equilibrium withthem, appear to influence expression of the IgG2molecule (85).This response appears to be race spe-cific (102), and young Caucasians of the low-re-sponder phenotype (G2m(null), synonymous withG2m("), G2m(-n) and G2m(-23), are predisposed tospecific bacterial infections (2). Approximately twoof three Caucasians are positive for G2m(23), andthese individuals have been shown to have highertotal levels of IgG2 and to have a higher IgG2 re-sponse to various polysaccharide antigens (32, 84,94, 114). There is also some indication that avidityof the IgG2 antibody is genetically influenced andrelated to the G2m(23) allotype (50).

The results of formal genetic studies (segregationanalysis) of IgG2 titer for members of 123 early-onsetperiodontitis families supports the existence of amajor locus that accounts for approximately 62% ofthe variance in IgG2. IgG2 levels were found to beelevated in localized juvenile periodontitis patients,but not in generalized forms of early-onset peri-odontitis, and IgG2 levels in African-Americans werehigher than in Caucasians, regardless of disease sta-tus. When adjustments are made for smoking andthe G2m(23) allotype, the best fitting genetic modelis a co-dominant major locus (68). These resultsstrongly support genetic control of IgG2 response.

Recently, Choi et al. (17) assessed allotypes for thefgG subclasses an d levels of IgG2 antibody to Actino-bacillus actinomycetemcomitans and Porphyromon-

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Genetic factors in the pathogenesis ofperiodon titisas gingivulis in localized juvenile periodontitis andrapidly progressive periodontitis patients. The rapid-ly progressive periodontitis patients who were posi-tive for the G2m(23) (synonymous with G2m(n))allotype had elevated antibody to I? gingiuulis. It isdifficult o determine the relationship of these find-ings to those of Marazita et al. (68), since diseasecriteria and race differed.

The markedly elevated serum IgG2 levels relatedto localized juvenile periodontitis status appear re-lated to a fundamental difference in the response ofleukocytes from African-American localized juvenileperiodontitis patients. Specifically, B cells fromAfrican-American localized juvenile periodontitispatients appear predisposed to produce high levelsof IgG2, but this response appears to be determinedin large part by monocytes (130). These data supportthe hypothesis that increased serum IgG2 wouldprovide sufficient protection against spread of A .actinomycetemcomituns to result in localized, ratherthan generalized, early-onset periodontitis. The opti-mal phagocytic efficiency of localized juvenile peri-odontitis serum, containing IgG2 antibodies, hasbeen shown to require neutrophils that express Fc-yreceptors capable of recognizing this antibody sub-class, as discussed below in section 4.2.

In addition to host factors, environmental factorsare capable of modulating IgG2 response. Cigarettesmoking is known to reduce serum IgG levels. Theeffect of smoking on serum immunoglobulin levelsare both race and serum IgG subclass specific. InAfrican-American generalized juvenile periodontitispatients who smoke, IgG2 and IgG4 levels are re-duced, whereas the IgG2 and IgG4 levels in African-American localized juvenile periodontitis and non-periodontitis subjects are not reduced by smoking(93).Thus, the effectiveness of antibody in protectingagainst A . actinomycetemcomituns appears to be in-fluenced by the serum level of IgG2 and the ex-pression of Fc-y receptors on the neutrophil, both ofwhich appear to be genetically determined.FcyRIIa receptor heterogeneityNormally functioning phagocytic cells comprise akey element of host response to microbial challenge.Human phagocytic cells communicate with their ex-ternal environment through surface receptors, suchas the Fc receptor that binds immunoglobulin. Poly-morphisms in Fc receptors (13,831 expressed on thesurface of phagocytic cells have been shown recentlyto be important determinants of susceptibility to in-

fections (98). The FcyRIIa (CD32) receptor recog-nizes the Fc region of IgG2, and therefore neutro-phils expressing this receptor are capable of recog-nizing bacteria that have been opsonized by IgG2.

The immunoglobulin Fc receptor I1 genes havebeen mapped to chromosome 1 (33), and the FcyIIAgene has two expressed alleles, which differ signifi-cantly in their ability to bind human IgG2. The twoalleles differ by the amino acid, arginine (R131) orhistidine (H131),at position 131 (121-123). Althoughthere are multiple Fcy receptors, H131 is the onlyFcy receptor that efficiently recognizes IgG2, and themaximum IgG2 binding is found in the homozygousH131 state (95).Individuals with low or intermediateaffinity CD32 receptors may manifest enhanced sus-ceptibility to infections by encapsulated bacteriasuch as meningococcal disease (14, 97).

The IgG2 response has been shown to be promi-nent in periodontitis (43). Although this subclass ofIgG has traditionally been viewed as being poorlyopsonic, recent work (13,99) demonstrates that IgG2has significant opsonic activity if used with phago-cytes expressing the H131 receptor. Wilson et al.(127, 128) have shown that localized juvenile peri-odontitis serum containing IgG2 antibodies are ef-fective in phagocytosing A. uctinomycetemcomituns,when used in conjunction with neutrophils that ex-press Fcy receptors capable of recognizing this im-munoglobulin subclass. IgG2 was significantly moreeffective in mediating phagocytosisof A . actinomyce-temcomitans, when used with human neutrophilsthat were homozygous for the H131 receptor as com-pared to neutrophils from individuals homozygousfor the R131 receptor (128). The genetic polymorph-ism that defines the FcyRII receptor, therefore, ap-pears to be a promising marker for susceptibility tolocalized juvenile periodontitis.

Mediators of inflammationProstaglandin E2. rostaglandins are potent biologi-cal mediators with diverse physiological effects thathave also been implicated in a variety of pathologicalconditions including periodontitis (78, 79). The en-zyme prostaglandin endoperoxide synthase convertsarachidonic acid to prostaglandin HZ,he precursorfor prostaglandins, prostacyclins and thromboxanes(108).There are two isoforms of the enzyme (prosta-glandin endoperoxide synthase 1 and 2) that havesimilar catalytic activity (47). Prostaglandin endop-eroxide synthase 1 is constitutively expressed inmost tissues and appears to generate prostaglandinsthat are involved in maintenance of essential physio-

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Hurt & Kornmanlogical functions (117). In contrast, prostaglandinendoperoxide synthase 2 is not constitutively ex-pressed but is rapidly induced in response to a var-iety of proinflammatory stimuli, including cytokines,growth factors and bacterial lipopolysaccharide (55,108). The prostaglandin endoperoxide synthase 2enzyme appears to be the predominant effector ofprostaglandin activity in inflammation (105).

Prostaglandin E2 has been implicated in adultperiodontitis and in early-onset periodontitis andmay mediate much of the tissue destruction that oc-curs in periodontal disease (78, 79). A recent study(120) identified linkage of the chromosome 9q32-33region with early-onset periodontitis. This physicalregion includes the gene for prostaglandin endop-eroxide synthase 1, and this observation encouragesfurther studies associating genetic markers ofprostaglandin E2 with clinical periodontitis.Interleukin 1. The immune system produces cyto-kines and other humoral factors to protect hosttissues from inflammatory agents, microbial in-vasion and injury. In most cases this complex de-fense network successfully restores normal homeo-stasis. However, at times the overproduction of im-munoregulatory mediators may actually proveharmful to the host (16). Genetic polymorphisms inregulatory regions of genes responsible for inflam-matory mediators may act to create interindividualdifferences in such responses. The similarity of cyto-kines in active and chronic lesions suggests thatquantitative rather than qualitative differences incytokine mediators may account for lesion pro-gression (119).

The interleukins are key mediators of inflam-mation and also modulate the extracellular matrixcomponents and bone that comprise the peri-odontal tissues (8, 113).Elevated tissue and gingivalfluid levels of interleukin 10 ( IL - l p ) in particularhave been repeatedly associated with periodontitis(56, 60, 92, 111, 129). Although the inflammatoryprocess generally increases the local tissue levels ofIL- 1, stable interindividual differences in cytokineproduction rates have been reported (21, 89).

A family of three IL-1 genes cluster on chromo-some 2q13. Two of these genes (IL-1A and IL-1B) en-code the pro-inflammatory proteins I L - l a and IL -10, whereas IL-1RN encodes a related protein thatfunctions as a receptor agonist (IL-Ira). Recentlyseveral genetic polymorphisms were described inthe genes of the IL-1 cluster, and significant associ-ations have been identified in case control studiesbetween several of these genetic polymorphisms and

an increased severity of inflammatory diseases (27).One of these genotypic polymorphisms (IL-1B at+3953) is associated with a fourfold increase in IL-l p production (25). Specifically, monocytes from in-dividuals with different alleles in the IL-1P +3953 lo-cus were compared for lipopolysaccharide stimula-tion of IL-10. Polymorphisms at this locus appear as-sociated with monocytic production of IL-1P asfollows: homozygous allele 1 /1 : 5.2 ng/ml, hetero-zygous allele 112: 12.4 ng/ml, and homozygous allele2/2: 19.9 ng/ml.

Kornman et al. (52) correlated severe adult peri-odontal disease in nonsmokers with a genetic haplo-type that includes allele 2 of the IL-1A-889 poly-morphism and allele 2 of the +3953 polymorphismof the IL-1B gene that has been associated with in-creased IL-1 production (52). The association be-tween the genetic polymorphism in IL-1 genes withsevere periodontitis is only evident when smokersare excluded. This study is the first to identify a gen-etic polymorphism that corresponds with a pheno-typic immune response variable (IL-1 production) inadult periodontitis patients. These data also supportthe importance of other environmental factors suchas smoking as a risk factor for periodontitis (35, 104).The association of severe periodontitis with smokingand the IL-1 genotype suggest that they play an im-portant role in the pathogenesis and clinical courseof adult periodontitis.

Neutrophil dysfunctionPolymorphonuclear neutrophils represent a majorcellular component of the innate cellular defensesystem in humans, particularly against bacterial in-fections. Several genetic defects which affect neutro-phi1 function are known to predispose for microbialinfections, and a number of these are associatedwith increased periodontitis (31, 40). For example,leukocyte adhesion deficiency type I, an autosomalrecessive trait that involves an inherited defect of theMac-1, LFA-1 and p150.95 glycoproteins, also knownas the CD11118 group (31, has been identified insome patients with generalized prepubertal peri-odontitis (86).

Chemotaxis disorders have been described as pri-mary or secondary to a number of diseases includingChediak-Higashi syndrome, diabetes mellitus, Papil-lon-Lef&vre yndrome, and several forms of early-on-set periodontitis (103). A substantial proportion ofpatients with localized juvenile periodontitis (ap-proximately 70%) appear to have a relative defect inthe ability of their peripheral blood neutrophils to

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Genetic factors in the pathogenesis of periodontitisrespond to chemotactic agents (116). Additionally,defective neutrophil killing of certain strains of A .actinomycetemcomitans has been reported in certainlocalized juvenile periodontitis patients (46). Thesefindings suggest that either general or specific neu-trophil defects may contribute to periodontitis sus-cep ibility.

Since several microbial diseases appear to becaused by defective cellular killing of specific mi-crobes (65) similar pathogenic mechanisms may beresponsible for some forms of early-onset peri-odontitis. A significant proportion of the interindi-vidual variance in immune response to microbialchallenges appears to be under genetic control, andvariants in neutrophil function are reasonable candi-dates for genetic determinants of increased suscepti-bility to periodontitis.

ConclusionThe pathogenesis of infectious diseases is regulatedby a complex interplay between microbes and theimmune system. The effectiveness of the immuneresponse depends on factors in both the internal andexternal environments, and clear evidence hasemerged for internal and external influences onperiodontal disease. For example, both smoking andgenetic control of cytokines appear to modulate thehost response to oral bacteria and influence peri-odontal disease susceptibility and clinical expression(35, 52, 79).

A significant paradigm shift has occurred in theperception of periodontal disease over the last 20years. Increasingly, the emphasis for risk is beingplaced on host genetic and other nonmicrobial en-vironmental factors as modifiers of the bacteriallyinduced disease. Although classical epidemiologicalstudies have clearly implicated a number of environ-mental, microbial and host factors in periodontaldiseases, the information has not yet translated intopractical models for estimating individual risk.

A multitude of host factors are involved in re-sponses to microbial challenge and in the sub-sequent immune responses. Genetic polymorphismsprobably exist in many if not most of the inflamma-tory and immune mediators. However, it is likelythat: 1) not all polymorphisms impart differentialsusceptibility to destructive aspects of the disease; 2 )a number of genes will be identified as important inthis regard; and 3) knowledge of these may permitdetermination of individual risk for many individ-uals. The key will be to identify those polymorph-

isms that are important enough to impart significantrisk for disease.

Correlation of genetic polymorphisms in immuneresponses with phenotypes for certain patientgroups, such as demonstrated by the FcyIIa receptorfor early-onset periodontitis and IL- 1 for adult peri-odontitis, currently appears to provide the mostpromising application of genetic determinants ofperiodontitis (52, 128). In the future it may be poss-ible to use such information to adjust the host re-sponse to microbial infection to maximally inhibitthe microbe while minimizing inflammatory damage(30).

Genetic polymorphisms are known to affect boththe qualitative and quantitative aspects of host re-sponse. Structural gene defects can affect the quali-tative response to microbes; however, regulatorypolymorphisms can alter the response quantitative-ly. Recent progress in the development of high-qual-ity genetic markers and high-density human geneticmaps shows promise in facilitating new strategies formapping disease-causing and disease susceptibilitygenes (65, 107). Correlation of these genetic poly-morphisms with stable phenotypic characteristics ofperiodontitis patient groups may provide the frame-work for identification of molecular biomarkers tobe incorporated into individual risk profiles and alsohelp to set the foundation for developing new treat-ment strategies.

AcknowledgmentsWe thank Elaine Robertson for manuscript prepara-tion. TCH received support for grants R29-DE11601and R01-DE06436 from the US National Institute forDental Research.

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