Review Article Genetic Aspects of Preeclampsia and the HELLP Syndrome · the HELLP syndrome and...

Review ArticleGenetic Aspects of Preeclampsia and the HELLP Syndrome

Kjell Haram1 Jan Helge Mortensen2 and Baacutelint Nagy3

1 Department of Obstetrics and Gynecology Haukeland University Hospital Bergen 5006 Norway2Department of Global Public Health and Primary Care University of Bergen Norway3 1st Department of Obstetrics and Gynecology Semmelweis University Budapest 1088 Hungary

Correspondence should be addressed to Kjell Haram kjellharambroadparkno

Received 30 November 2013 Revised 27 February 2014 Accepted 1 April 2014 Published 2 June 2014

Academic Editor Jeffrey Keelan

Copyright copy 2014 Kjell Haram et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Both preeclampsia and the HELLP syndrome have their origin in the placenta The aim of this study is to review genetic factorsinvolved in development of preeclampsia and the HELLP syndrome using literature search in PubMed A familial cohort linkschromosomes 2q 5q and 13q to preeclampsia The chromosome 12q is coupled with the HELLP syndrome The STOX1 gene theERAP1 and 2 genes the syncytin envelope gene and the minus670 Fas receptor polymorphisms are involved in the development ofpreeclampsia The ACVR2A gene on chromosome 2q22 is also implicated The toll-like receptor-4 (TLR-4) and factor V Leidenmutation participate both in development of preeclampsia and the HELLP syndrome Carriers of the TT and the CC genotypeof the MTHFR C677T polymorphism seem to have an increased risk of the HELLP syndrome The placental levels of VEGFmRNA are reduced both in women with preeclampsia and in women with the HELLP syndrome The BclI polymorphism isengaged in development of the HELLP syndrome but not in development of severe preeclampsia The ACE ID polymorphismaffects uteroplacental and umbilical artery blood flows in women with preeclampsia In women with preeclampsia and the HELLPsyndrome several genes in the placenta are deregulated Preeclampsia and the HELLP syndrome are multiplex genetic diseases

1 Introduction

Preeclampsia is a multisystemic disorder in pregnancy withde novohypertension andproteinuria occurring after the 20thgestational week and is characterised by hypertension andproteinuria with or without oedemaThe condition is associ-ated with a reduced plasma volume hemoconcentration andincreased vascular resistance One of the chief targets is thekidneys and the clinical picture is dominated by hypertensionand proteinuria [1ndash3] The clinical findings of preeclampsiacan manifest as either a maternal syndrome (hypertensionand proteinuria with or without other multisystem abnor-malities) or fetal syndrome (fetal growth restriction reducedamniotic fluid and abnormal oxygenation) [3]The conditionmay cause serious maternal and fetal complications [3]

Women with preeclampsia may develop the HELLP syn-drome (haemolysis elevated liver enzymes and low platelet)which occurs in 05 to 09 of all pregnancies and in 10to 20 of women with severe preeclampsia The syndromemay be complete or incompleteThemajority of women with

the HELLP syndrome have hypertension and proteinuriabut the condition may also occur without these [4] Typicalclinical symptoms of the HELLP syndrome are right upperabdominal quadrant or epigastric pain nausea and vomitingThe upper abdominal pain may be fluctuating colic-like Upto 30ndash60 has headache and about 20 visual symptomsIn the postpartum period the HELLP syndrome usuallydevelops within the first 48 hours in women who have hadproteinuria and hypertension prior to delivery Excessiveweight gain and generalized edema precede the syndrome inmore than 50 of the cases [4] However it is important torecognize thatwomenwith aHELLP syndrome alsomay haveunspecific symptoms subtle signs or viral syndrome-likesymptoms which should not be overlooked Many womenreport a history ofmalaise some days before presentationTheHELLP syndrome may cause different maternal fetal andneonatal complications which may be serious [4]

Preeclampsia and the HELLP syndrome present as symp-tomless placental conditions in the first hand and then as

Hindawi Publishing CorporationJournal of PregnancyVolume 2014 Article ID 910751 13 pageshttpdxdoiorg1011552014910751

2 Journal of Pregnancy

a maternal syndrome with lesions in different organs andvarious clinical symptoms [5]

Preeclampsia may occur without a fetus in the case ofhydatidiform mole [6] It is established that preeclampsiaoriginates in the placenta [3 7 8] It is conceivable that theHELLP syndrome also is a placenta-dependent condition[9 10] Following delivery of the placenta the maternal symp-toms and signs of preeclampsia often disappear but a pro-tracted course of a severe HELLP syndrome is not unusual[11]

A variety of molecular factors are involved in the patho-physiology of preeclampsia and the HELLP syndrome Theaim of this publication is to present a review and a com-prehensive description of the genetic factors involved and tosuggest modes of action in development of preeclampsia andthe HELLP syndrome

2 Search Strategy

An unsystematic search in PubMed was conducted by usingthe search words ldquopreeclampsiardquo or ldquoHELLPrdquo combined withldquoetiologyrdquo or ldquogenerdquo or combined with risk factors respec-tively (2000ndash2013) Abstracts were read and the publicationcited if it was considered adequate

3 Risk Factors for Preeclampsia andthe HELLP Syndrome

Several risk factors have been identified with increased riskof preeclampsia Preeclampsia is generally regarded as adisease of the first pregnancyThe risk factors include chronichypertension renal diseases obesity and insulin resistancediabetes mellitus preexisting thrombophilia family historyof preeclampsia and smoking [3] High body mass index(BMI) and metabolic syndrome 6 months postpartum wereassociated with preeclampsia but hardly with HELLP [12]

Most white womenwithHELLP aremultiparousWomenwith a HELLP syndrome are more likely than those in thecontrol group to be gt35 years old (33 compared with22) be nulliparous (67 compared with 43) have hada previous gestational hypertensive disorder (9 comparedwith 7) and have a multiple pregnancy (7 compared with2) [13]

The risk of preeclampsia increases in those who havelimited sperm exposure with the same partner before con-ceptionMost epidemiologic studies demonstrate that regularsexual intercourse of an extended period reduces the risk[14 15] Women with a history of abortion who conceivedagain with the same partner had nearly half the risk ofpreeclampsia compared to women without a history of abor-tion In contrast women with an abortion history who con-ceived with a new partner had the same risk as womenwithout a history of abortion [16]

31 The ldquoRoot Causerdquo Preeclampsia and the HELLP syn-drome both originate in the placenta [17] The ldquoroot causerdquoof preeclampsia is thought to be reduced placental perfusion[18] It has been demonstrated that impaired extra villoustrophoblasts (EVTs) invasion in the decidua and the spiral

arteries and insufficient spiral artery remodeling may takeplace both in women with preeclampsia and in women with aHELLP syndrome [19] Reduced placental perfusion interactswith preexisting maternal disorders such as hypertensionrenal disease overweight diabetes mellitus obesity lipidabnormalities and insulin resistance This will affect thematernal susceptibility to preeclampsia because it liberatesbioactive factors which pass through the intervillous spaceinto thematernal circulation inducing an inflammatory reac-tion and endothelial dysfunction [20ndash22]

HELLP and preeclampsia become clinically manifestduring the second (early-onset form) or third trimester (late-onset form) of pregnancy but the initiating event occursmuch earlier in gestation [23] The resultant symptomaticsecond stage of preeclampsia thematernal syndrome usuallydevelops after the 20th gestational week [8 24] The HELLPsyndrome is also associated with widespread organ damagewith different clinical signs in the second stage [4 10]

However implantation disorders can be detected in thefirst trimester before 12 to 20 weeksrsquo gestation when the deepinvasion of EVT and spiral artery remodeling occur and priorto failed vascular remodeling of the spiral arteries necessaryto reduce placental perfusion [22 25] In some cases ofpreeclampsia and a HELLP syndrome aberrant restructuringof the uterine spiral arteries by invading trophoblasts betweenweeks 8 and 12 of gestation ultimately causes poor placentalperfusion and placental ischemia [26] Thus factors whichincrease the risk of preeclampsia and are associated withabnormal implantation in early pregnancymight be the ldquorealrdquoldquoroot causerdquo of preeclampsia [22 25]

4 Genetic Considerations

41 Epidemiologic Studies It has been recognised for manyyears that preeclampsia has different genetic components[27] Both maternal and fetal genes appear to play etiolog-ical roles Evidence for a role for paternally inherited fetalgenomes comes from an analysis of data from the NorwegianMedical Birth Registry from 1967 to 1992 which identifiedalmost 400000womenwho had had at least two pregnanciesIt was possible from the records to distinguish between apregnancy with the same parents and those where themotheror the father differed in the second pregnancy [28] In the firstpregnancies the risk of preeclampsia was above 3 slightlyincreasingwithmotherrsquos ageThe riskwas 17 among secondpregnancies inmothers who had their second pregnancywiththe same partner and 19 among second pregnancies inmothers who had changed their partner since the first preg-nancy [28] Men who were born from a preeclampsia preg-nancywere at risk of fathering a preeclampsia pregnancy [29]First degree female relatives of womenwith preeclampsia hada 5-fold higher risk and seconddegree relatives a 2-fold higherrisk of developing preeclampsia thanwomenwithout a familyhistory of preeclampsia [30] Studies of familial aggregationof preeclampsia indicate that genetic factors may contributemore than 50 of the variability in liability to preeclampsia[31 32]

Women with a history of HELLP are at increased riskof preeclampsia (22ndash28) and a HELLP syndrome (14ndash24)

Journal of Pregnancy 3

in subsequent pregnancies suggesting related pathogenicmechanisms [33 34] Sisters and children of a woman whohas sustained a HELLP syndrome have increased risks ofdeveloping a HELLP syndrome in pregnancy [35]

5 Candidate Genes

In 1999 the results of a genome-wide scan of Icelandic fami-lies which included 124 pedigrees of 343 women affected bypreeclampsia were published byArngrımsson et alThe studyrevealed a maternal susceptibility locus for preeclampsia onchromosome 2p13 [36] A genetic linkage to chromosomes2q 5q and 13 q was demonstrated in an AustralianNewZealander familial preeclampsia cohort [37] In a study byLachmeijer et al a genome-wide scan of Dutch affectedsib-pair families uncovered a peak on chromosome 12qwhich was associated with the HELLP syndrome It increasedto a lod score of 21 in the HELLP families and almostdisappeared in families with preeclampsia This means thatthe HELLP syndrome and preeclampsia have a differentgenetic background [35]

Susceptibility genes at the 5q gene locus were also cen-tered in a spectrum of families in a Norwegian preeclampsiacohort (1139 cases and 2269 controls) using (SNP) genotyp-ing [37]There was also evidence of a genetic association withpreeclampsia for the endoplasmatic reticulum aminopepti-dases 1 and 2 (ERAP1 and 2) genes The ERAP1 and ERAP2genes encode enzymes that play roles in blood pressureregulation via involvement of the renin-angiotensin system inaddition to the innate immune system [37] The ERAP1 genecleaves the cell surface receptors for the proinflammatorycytokine interleukin-1 (IL-1) IL-6 and the tumor necrosisfactor120572 (TNF-120572) thereby downregulating their signalingTheERAP1 gene can therefore have proinflammatory effects [37]

An association between the susceptibility activin recep-tor type 2 gene (ACVR2A) on chromosome 2q22 andpreeclampsia (119899 = 1139) was demonstrated in the Nor-wegian cohort DNA samples from 1139 cases (women withone or more preeclamptic pregnancies) and 2269 controls(women with normal pregnancies) were genotyped usingthe Applied Biosystems SNPlex high-throughput genotypingassay [38] The fact that populations with different ances-tors (IcelandNorway-AustraliaNew Zealand) demonstratea common maternal preeclampsia susceptibility locus onchromosome 2q22 may suggest a general role of this locus inthe pathophysiology of preeclampsiaTheACVR2A genemayaffect the activin A activity which is involved in EVT invasionin the decidua and the spiral arteries as well as in remodelingof the spiral arteries [38]

Goddard et al conducted a large scale study evaluating775 single nucleotide polymorphisms (SNPs) in 190 genes inwomen with preeclampsia (119899 = 294) and their offspring (119899 =324) [39] SNPdiscoverywas performed byDNA sequencingand genotyping was carried out in a high-throughput facilityusing the MassARRAY TM System The most significantfindings for an association with preeclampsia were thecollagen type I alpha 1 (COL1A1) and IL1A genes for thematernal genotype and the plasminogen activator urokinasereceptor gene (PLAUR gene) for the offspring genotype

Notably common candidate genes for preeclampsia includ-ing methylene-tetrahydrofolate reductase (MTHFR) andnitric oxide synthase 3 (NOS3) were not significantly asso-ciated with preeclampsia [39]

Buimer et al performed a study of the gene expressionin placental tissues from normotensive pregnant women andwomen with preeclampsia and a HELLP syndrome Firstlycomparison of Serial Analysis of Gene Expression profilesof 28 weeksrsquo control placenta (available after idiopathic pre-mature delivery) to a HELLPpreeclampsia placenta matchedfor gestational age identified 404 differentially expressedtranscripts Secondly using sequential PCR the expressionlevels of 37 of these transcripts in the placentas of healthypregnantwomen (119899 = 36) and in the placentas of womenwithpreeclampsia and a HELLP syndrome (119899 = 22) were anal-ysed Thirdly nearest centroid classification determined theHELLP specific molecular signature consisting of the upreg-ulated expression of genes encoding the vascular endothelialgrowth factor receptor (FLT1) leptin (LEP) pappalysin 2(PAPPA2) andWWdomain containing transcription regula-tor 1 (WWTR1) combined with downregulated expression ofthe genes encoding cadherin-associated protein (CTNNAL)glutathione S-transferase pi (GSTP1) and calgranulin A(S100A8)This set discriminates theHELLPplacenta from theplacenta of healthy women and the placenta of women withpreeclampsia with a 24 misclassification rate independentof known risk factors like parity and ethnicity [23]

6 Some Selected Genes and Occurrence ofPreeclampsia and HELLP

In the following the influences of different genes on develop-ment of preeclampsia and the HELLP syndrome accordingto various publications are presented Genome-wide associ-ation studies (GWAS) have disclosed susceptibility genes forpreeclampsia The results seem compatible with the assump-tions that unfavourable gene variants and interactionsbetween genes regulating maternal-fetal interactions areinvolved in development of preeclampsia Table 1 summarizesselected gene effects on preeclampsia and the HELLP syn-drome obtained after unsystematic search in PubMed

7 The STOX1 Gene

The 10q22 chromosomal region with genomic linkage topreeclampsia in Dutch females shows a parent-of-origineffect with maternal transmission of Y153H susceptibilityallele of the STOX1 gene [55] The STOX1 gene which isplacentally expressed was identified as a candidate gene forpreeclampsia (119899 = 157) in a Dutch population [56] Twostudies (2007) in both a Dutch and a Finnish population didnot support or confirm that the STOX1 gene was involved indevelopment of preeclampsia [57 58] However the roles ofSTOX1 on trophoblasts dysfunction have been confirmed inseveral studiesThe STOX1 gene is a key player in trophoblastdysfunction underlying early-onset preeclampsia [56 59ndash61]There does not seem to be any study which focuses on theSTOX1 gene and development of the HELLP syndrome


Table 1 Gene types connected to preeclampsia and the HELLP syndrome-mode of actions

Gene Effect on preeclampsia or the HELLP syndrome References

The STOX1 gene A key player in trophoblast dysfunction underlying early-onset preeclampsia [40]

Syncytin envelope gene A reduced expression may disturb placental function and increase rate of apoptosisin cytotrophoblasts

[41]

MBL gene polymorphismExcessive MBL-mediated trophoblast damage may cause insufficient EVT invasionof the spiral arteries Maternal heterozygosity at codon 54 of the MBL B alleleprotects against preeclampsia and HELLP

[42]

Factor V Leiden mutation Increase risk of preeclampsia and HELLP [43 44]

MTHFR C677Tpolymorphism Involved in development of the HELLP syndrome [45]

G0210A mutation of factorII (prothrombin) gene Involved in development of preeclampsia [46 47]

The VEGF TT-460 SNPgenotype

Carriers had an increased risk of HELLP syndrome and could play a role indevelopment of the HELLP syndrome

[48]

ACE IID polymorphism

The renin-angiotensin system is a mediator of the EVT invasion and remodeling ofthe spiral arteriesThe ACE ID polymorphism seemed to affect the uteroplacental and umbilicalartery (UA) blood flows and the recurrence of preeclampsia

[49]

BclI polymorphism of theGR gene

The BclI polymorphism is associated with development of HELLP syndrome butnot of severe preeclampsia

[50]

Polymorphism of EPHXgene

High activity genotype in exon 3 which could reflect differences in metabolicactivation of endogenous or exogenous toxic compounds may have enhancedsusceptibility to preeclampsia

[51]

NFRSF6-670polymorphism

Homozygous carriers with the -670 AG or GG genotype are more likely to developthe HELLP syndrome than those homozygous for the wild type of the Fas receptor(TNFRSF6-670AA)

[52]

TLFR-4 gene TLR-4 pathway and the innate immune system might be involved in developmentof both early-onset preeclampsia and the HELLP syndrome

[53]

Leptin gene (LEPR) The LEPR gene and its serum level correlate with the leptin concentration inperipheral blood The LEPR gene is transcribed in the villous and EVTs

[54]

8 The Syncytin Envelope Gene

The creation of the syncytium layer by cytotrophoblastsis an important step in the placentation process Syncytinenvelope gene is an essential gene mediating the cytotro-phoblast cell-cell fusion and differentiation [40 62 63]Decreased syncytin expression in cytotrophoblasts impairsthe syncytiotrophoblast formation [64] A study by Knerr etal included women with preeclampsia (119899 = 16) women witha HELLP syndrome (119899 = 6) and healthy pregnant women(119899 = 30) After delivery mRNA of syncytin glyceraldehyde-3-phosphate dehydrogenase and 120573-actin were analyzed inplacental villi with use of quantitative real-time PCR Thesyncytin mRNA levels were significantly lower in the chori-onic villi in womenwith preterm preeclampsia and inwomenwith the HELLP syndrome than in women with healthypregnancies A reduced placental expression of syncytinmay contribute to altered cell-cell fusion processes in theplacentogenesis and to a disturbed placental function [65]

The placenta was analyzed in a study by Langbein et alcomprising women with preeclampsia and IUGR (119899 = 8)and women with the HELLP syndrome and IUGR combined(119899 = 8) Total RNA was extracted from 50 to 100mg

of frozen placental tissues by mincing using a Mikro-Dismembranator (Braun Biotech Sartorius AG GoettingenGermany) and purified using Trizol1 reagent (InvitrogenKarlsruhe Germany) The syncytin envelope placental geneexpression in women with preeclampsia combined withIUGR was 54-fold lower and in women with the HELLPsyndrome associated with IUGR was 106-fold lower alongwith a 18- and 19-fold significant increase in the apoptosisrate in the cytotrophoblasts compared with control subjectsrespectivelyThis higher rate of apoptosismay be contributingto an inflammatory response [66]

9 Mannose-Binding Lectin (MBL)Gene Polymorphism

Insufficient invasion of the spiral arteries by trophoblast cellsis associatedwith the etiology of preeclampsia and theHELLPsyndrome Mannose-binding lectin (MBL) is a componentof the innate immune system The MBL gene is locatedon chromosome 10 and is polymorphic at codons 52 54and 57 MBL is present in the spiral arteries particularly inthose containing endovascular trophoblasts MBL-mediated


activation of the complement cascade is an important eventin destruction of invading EVTs [67]

Carriers of the MBL-54 B variant have been reported in22ndash28 of European and North American populations [67]ExcessiveMBL-mediated trophoblast damagewould increasethe possibility of insufficient EVT invasion of the spiralarteries The subsequent hypoxia could initiate a sequence ofevents culminating in preeclampsia [67]

A study by Sziller et al comprised women with pree-clampsia (119899 = 51) women with the HELLP syndrome (119899 =81) and healthy pregnant women (119899 = 184) DNA wasextracted from buccal swabs of women with preeclampsiawomen with HELLP syndrome and healthy pregnant con-trols Aliquots were tested for a single nucleotide MBL genepolymorphism at codon 54 by PCR and endonuclease diges-tion There was significantly higher number of the TT geno-type (25) in women with the HELLP syndrome than inwomen with severe preeclampsia (9) and in healthy (8)pregnant women It was suggested that maternal heterozy-gosity at codon 54 of the MBL B allele was protectiveagainst development of preeclampsia and HELLP syndromeHomozygosity for the wild type allele A of the MBL-54 genewas more frequent among women with preeclampsia and theHELLP syndrome Carriage of the variant B allele was alsoprotective against development of IUGR in women with bothpreeclampsia and HELLP syndrome [67]

10 Factor V Leiden Mutation

Thrombosis and atherosis of the spiral arteries are often foundin the placenta of women with preeclampsia the HELLP syn-drome and IUGR [41 42] Women with a HELLP syndromealso had frequent acute atherosis in spiral arteries invaded byEVTs and in noninvaded spiral arteries (Robert Pijnenborgpersonal communication) Factor V Leiden mutation is thecause of resistance to activated protein C which may lead tointravascular coagulation

Lin and August performed a meta-analysis on geneticthrombophilias and preeclampsia assessing the relationshipbetween the factor V Leiden (1691 G-A) SNP the methylenetetrahydrofolate reductase (MTHFR) 677 C-T SNP and theprothrombin 20210 G-A SNP in all case-control studies withdata on these polymorphisms [68] All investigations usedPCR reaction and restriction fragment length polymorphismanalysis of DNA obtained from blood or buccal cells in thecase-control studies The pooled odds ratio (OR) for theassociation of factor V Leiden mutation and all women withpreeclampsiawas 181 (95) confidence interval (95CI 114ndash287) and 224 (95 CI 128ndash394) for women with severepreeclampsia [68]

A publication from 2008 revealed a clear relationshipbetween factor V Leidenmutation and womenwith a HELLPsyndrome Genotyping of the thrombophilic mutations wasperformed using the LightCycler technology Maternal het-erozygosity for factor V Leiden mutation was significantlymore prevalent in women with a HELLP syndrome (119899 = 71)than in healthy control women (119899 = 79) (OR 445) (Table2) [69] No significant association was observed for maternalprothrombinmutation orMTHFR polymorphismThe study

confirmed that women heterozygous for factor V Leiden havean increased risk of developing aHELLP syndrome while themost frequent mutations of the prothrombin and MTHFRgene did not play a major role in the pathogenesis [69]

11 MTHFR Polymorphism HomocysteinePreeclampsia and HELLP

It has been shown that alterations in the methionine homo-cysteine metabolism may be related to the systemic damagethat leads to the classical clinical picture of preeclampsia[74] A recent study evaluates the role of key enzymes inthe methionine-homocysteine metabolism (MHM) in thephysiopathology of preeclampsia Plasma and placenta frompregnant women (32 controls and 16 preeclamptic women)were analysed after informed consent Protein was quantifiedby western blot RNA was obtained with RNA purificationkit and was quantified by reverse transcriptase followed byreal-time PCR Identification of the C677T and A1298Cmethylene tetrahydrofolate reductase (MTHFR) SNPs andA2756G methionine synthase (MTR) SNP was performedusing PCR followed by a high-resolution melting analysisIt was shown that women who develop preeclampsia areclinically distinguishable at 11ndash14 weeks of gestation Keyenzyme RNA expression is increased in preeclamptic womenbut this change is not reflected at the protein contentThese results highlight a potential role of the MHM as acompensation mechanism in the presence of low levels of 2-methoxyestradiol (2-ME) [74]

The MTHFR gene plays a role in the metabolism ofhomocysteine Nagy et al conducted experiments on iso-lated DNA samples from the blood of women with severepreeclampsia (119899 = 101) women with the HELLP syndrome(119899 = 63) and healthy pregnant women (119899 = 73)TheMTHFRC677T polymorphism was determined by quantitative real-time PCR The mutant T allele was found in 45 of womenwith the HELLP syndrome in 32 of the healthy pregnantwomen and in 30 of women with severe preeclampsia [43]The results showed no difference in the distribution of theMTHFR C677T genotypes between the healthy controls andwomen with preeclampsia In the study however there wasa substantial difference between the incidences of MTHFR677T genotype among HELLP syndrome women and theother two study groups Thus the MTHFR C677T poly-morphism might be involved in development of the HELLPsyndrome [43]

12 Factor V Leyden MutationG0210A Mutation in the Factor II(Prothrombin) Gene and MTHFR inWomen with Thrombophilia

The mutation of the prothrombin gene is associated with anincreased risk of both venous and arterial thromboembolismSevere preeclampsia the HELLP syndrome and IUGR areassociated with intervillous andor spiral artery thrombosisand inadequate placental perfusion A congenital throm-bophilia disorder is the G0210A mutation in the factor II


Table 2 OR impact on preeclampsia and HELLP

Gene variant Preeclampsia compared to HELLP compared to Number OR (95 CI) References

Factor V Leiden mutation Healthy pregnancy 71 445 (131ndash1531) [69]Factor Leiden mutation169G-A SNP

Healthy pregnancy 1798 181 (114ndash287) [70]

Factor V Leiden mutation Healthy pregnancy 32 229 (056ndash932) [45]

Factor II prothrombin mutation Healthy pregnancy 32 603(065ndash4754)

[45]

Three mutations Healthy pregnancy 7522 184 (114ndash287) [71]

MTHFR 677C-T SNP Healthy pregnancy 2250 101 (079ndash129) [1]

VEGF C minus460T SNP Healthy pregnancy 71AdjustedOR 395

(151ndash608)[72]

VEGFG 405C SNP Healthy pregnancy 71AdjustedOR 367(105ndash175)

[72]

BclI polymorphism of GR gene Healthy pregnancy 17AdjustedOR 289

(145ndash574)[49]

BclI polymorphism of GR gene Severe preeclampsia 150 256 (145ndash574) [49]

Polymorphism of EPHX gene Healthy pregnancy 87 20 (12ndash37) [49]

Fas TNFRSF6 gene Healthy pregnancy 84 27 (12ndash59) [51]

TLR-4 gene Healthy pregnancy 177 41 (17ndash98) [52]Combined TLR-4 and NOD2 variant and highlevels of IL-6


III genotype of LEPR gene Healthy pregnancy 40 38 (08ndash180) [73]

LEPR 223G allele LEPR 23AAgenotype 24 192 (107ndash341) [54]

(prothrombin) gene which may lead to higher prothrombinproduction and to an increased risk of thrombosis [75]

A case-control study was performed by Benedetto et alcomprising women with preeclampsia (119899 = 111) and womenwith normal pregnancies (119899 = 111) matched for age andparity without previous thromboembolic disorders [45] Thewomen were tested for the A1691G mutation in the factorV Leyden mutation and the G20210A mutation of the factorII (progesterone) genes was amplified by PCR with PerkinElmer Gene Amp 2400 (New Jersey USA) Factor V Leidenmutation was found in a few women with preeclampsia andin healthy controls Factor II G20210A mutation was alsodetected in some women with preeclampsia [45] In thesubgroup of women with the HELLP syndrome (119899 = 32)factor V Leiden mutation was detected in 3 women (93)and factor II G20210A in 2 (62) Thus the prevalence offactor V Leyden mutation OR 229 (056ndash932) and factorII mutations OR 603 (065ndash4754) was increased in womenwith preeclampsia The thrombophilia mutations may inter-act with other pathogenic factors to determine the clinicalfeatures of the diseases and its complications [45]

In another study by Kupferminc et al women were testedseveral days after delivery for the mutation of adenine toguanine at nucleotide 506 in the factor V gene (factor VLeiden) the mutation of cytosine to thymine at nucleotide677 in the gene encoding MTHFR and the mutation of

guanine to adenine at nucleotide 20210 in the prothrombingene the prothrombin gene G20210A mutation [76] TheG20210Amutation was found to occur more often in womenwith complications such as preeclampsia (119899 = 11) than inwomen without complications (119899 = 3) (10 versus 3 resp)Overall 57 of the 110 women with obstetrical complications(52 percent) had at least one of the three thrombophilicmutations as comparedwith 19 of the 110womenwith normalpregnancies (17 percent) (OR 52 95 28 to 96) [76]

13 Vascular Endothelial Growth Factor(VEGF) Preeclampsia and HELLP

VEGF is produced by cytotrophoblasts and villous syncy-tiotrophoblasts in the placenta [46] VEGF is an endothelialcell-specific growth factor and a regulator of physiologicaland pathological angiogenesis [47] Nagy et al performeda study to determinate three VEGF SNPs The allele andgenotype frequencies of VEGF C minus460T SNP were deter-mined in the maternal blood DNA was isolated by usinga silica adsorption method The SNPs were determined byquantitative real-time PCR and melting curve analysis usingLightCycler Both carriers of the minus460TT and the +405CCgenotype of VEGF receptor genotype seemed to have anincreased risk of development of a HELLP syndrome (119899 =71) compared to healthy controls (119899 = 93) There were


significant differences in the allele and genotype frequenciesof VEGF C minus460T SNP between the two study groups The Tallele was present in 71 in the HELLP group and in 54 ofthe healthy controls The TT genotype occurred significantlymore frequently in the HELLP group than in the controlgroup (45 versus 22) The TT genotype carriers had anincreased risk of HELLP syndrome which was independentof maternal age and primiparity (adjusted OR 395) (Table 2)Although the VEGF G +405C allele and genotype distribu-tions did not differ significantly between the two groups theCC genotype carriers were also found to have an increasedrisk of HELLP syndrome after adjustment for maternal ageand primiparity (adjusted OR 367) (Table 2) The VEGF Cminus2578A SNP was not associated with the HELLP syndromeThe findings suggest that the VEGF polymorphisms inter-acting with other genetic and environmental factors couldplay a role in the development of the HELLP syndrome[77]

Sgambati et al performed a study to determine theexpression of VEGF in the placental tissue from pregnanciescomplicated by hypertension disorders of different clinicalseverity [72] Placentas from women with gestationalhypertension (119899 = 20) preeclampsia (119899 = 20) andpreeclampsia with HELLP syndrome (119899 = 20) and from nor-motensive women (119899 = 20) were analyzed as a control group(gestational age comprised between 35 and 38 weeks) Animmunohistochemical technique and a quantitative real-timePCR analysis to measure mRNA levels were employed Thelevels ofVEGFmRNAwere higher inwomenwith gestationalhypertension and lower in women with preeclampsia withHELLP syndrome compared to the levels of VEGF mRNAin control women [72] The different expression of VEGF inthe placenta of the pathological cases is probably related tohemodynamic changes that take place in these disorders inorder to attempt restoration of a normal uteroplacental flow[48]

14 The Angiotensin-Converting Enzyme(ACE) ID Polymorphism

Local prostacyclin stimulates the uteroplacental renin-angio-tensin system (RAS) and induces release of angiotensin-II(Ang-II) from trophoblastsThis improves the uteroplacentalblood flow by increasing perfusion pressure and by formingan extra stimulus of prostacyclin and nitric oxide (NO)release from uteroplacental vessels [48 78]

The renin-angiotensin system is one of the mediators ofthe EVT invasion and remodeling of the spiral arteries In astudy women with preeclampsia (119899 = 106) were genotypedfor theACE ID polymorphismGenomicDNAwas extractedfrom leukocytes using aQIAmpBloodKit (QIAGENHildenGermany) [79]TheACE ID polymorphism seemed to affectthe uteroplacental and umbilical artery (UA) blood flowsand the recurrence of preeclampsia The UA resistance indexwas significantly lower in the II genotype higher in DDand intermediate in ID genotype carriersThe UA pulsatilityindex values were significantly higher in the DD groupthan in the ID and II genotype [79] It was concludedthat in women with a history of preeclampsia the ACE

ID polymorphism affects both uteroplacental and umbilicalblood flows and the recurrence of preeclampsia [79]

15 The BclI Polymorphism ofthe Glucocorticoid Receptor (GR) Gene

The glucocorticoid receptor (GR) gene is the receptor towhich cortisol and other glucocorticoids bind The GR geneis expressed in almost every cell in the body and regulatesgenes controlling the developmentmetabolism and immuneresponse A study by Bertalan et al comprised healthy preg-nant women (119899 = 300) women with severe preeclampsia(119899 = 150) and women with a HELLP syndrome (119899 = 17)[80] Total genomic DNAwas isolated from peripheral bloodlymphocytes using a QIAamp DNA Blood Mini Kit (QiagenGmbH Hilden Germany) and the blood spot samples weredenatured by heat inactivation The BclI and the N363Spolymorphisms of the GR gene were determined by allele-specific PCR There were no significant differences in car-rier and allelic frequencies of the N363S and ER2223EKpolymorphisms between healthy pregnant women and thosewith severe preeclampsia However the allelic and carrier fre-quencies of the BclI polymorphism were significantly higherin women with HELLP syndrome compared to healthy preg-nant women (OR 289) and compared to those with severepreeclampsia (OR 256) (Table 2) The observations suggestthat among pregnant women the BclI polymorphism isassociated with development of theHELLP syndrome but notof severe preeclampsia Interestingly the BclI carrier statushad a significant impact on clinical laboratory parametersof women with the HELLP syndrome The aspartate amino-transferase (AST) lactate dehydrogenase (LDH) and alkalineprotease (ALP) levels were significantly higher whereas theplatelet count tended to be lower in BclI carriers than innoncarriers [80]

16 Polymorphism of Microsomal EpoxideHydrolase Gene (EPHX)

Genetic polymorphisms have been described in the humangene encoding for microsomal EPHX Two of these polymor-phisms 113TyrrarrHis in exon 3 and 139HisrarrArg in exon 4are associated with either a decreased or an increased enzymeactivity respectively [49] A study by Zusterzeel et al from2001 focused on whether or not the genetic variability inthe EPHX gene could contribute to preeclampsia and theHELLP syndrome Genomic DNA was isolated from wholeblood using the WizardTM genomic DNA purification kit(PromegaMadisonWIUSA) Amore frequent high activitygenotype Tyr113rarrTyr113 in exon 3 (29) was found inwomen with preeclampsia than in control subjects (16)(OR 20) (Table 2) In women with a history of preeclampsiano difference in epoxide hydrolase genotypes was foundbetweenwomenwho either did or did not develop theHELLPsyndrome [49] Women with the high activity genotype inexon 3 which could reflect differences inmetabolic activationof endogenous or exogenous toxic compounds may haveenhanced susceptibility to preeclampsia [49]


17 Polymorphism of the Fas Receptor

Fas and Fas Ligand (FasL) are classical transmembrane pro-teins that belong to the tumour necrosis factor receptorsuper family (TNFRSF) FasL is localized to both syncytiotro-phoblasts and cytotrophoblasts in the placental chorionicvilli [50] FasL and its receptor Fas are known to play animportant role in regulation of the immune response Fas ishighly expressed on activated T cells B cells NK cells andmacrophages [50] Sziller et al reported that a single adenine(A) to guanine (G) polymorphism at position minus670 in theFas receptor (TNFRSF6) results in decreased Fas synthesisA study by Sziller et al comprised women with a HELLPsyndrome (119899 = 84) and normotensive women (119899 = 83)[51] Cells from the buccal mucosa were obtained by rotatingcotton swab within 1 hour after delivery Genotype andallele frequencies were determined by direct counting andthen dividing by number of chromosomes to obtain allelefrequency and by the number of women to obtain genotypefrequencies [51] It was found that homozygous carriers withthe minus670 AG or GG genotype were more likely to develop theHELLP syndrome than those homozygous for thewild type ofthe Fas receptor (TNFRSF6minus670AA) (OR 27) (Table 2) [51]The TNFRSF6minus670 polymorphism is linked to decreasedapoptotic potential of maternal T cells due to polymorphismin the Fas receptor at minus670 which is thought to contribute to aprolonged capacity ofmaternal lymphocytes to recognize anddestroy EVTs during invasion of the decidua and the spiralarteries which may lead to development of preeclampsia orHELLP syndrome [51]

18 Maternal TLR-4 and NOD2 Gene

Toll-like receptors (TLR) are considered to be the mostimportant class of pattern-recognition receptors (PRRs)involved in host defence against a variety of microbes TLRsare central components of the innate immune system [81]Toll-like receptors (TLRs) are central components of theinnate immune system [81] The allelic variants of the innateimmune system the toll-like receptor-4 (TLR-4) and theNOD2 gene (an apoptosis regulator) variants were investi-gated by van Rijn et al 6months after delivery in primiparouswomen with a history of an early-onset preeclampsia (119899 =340) of whom 177 developed the HELLP syndrome 113women with an uneventful pregnancy were controls [52]Genomic DNA was isolated from blood using standardcommercially available kits (Gentra Systems MinneapolisMN USA) Two common missense mutations of the TLR-4gene (GenBank NM 138554 OMIM 603030) were detectedby PCR The highest frequency of the TLR-4 was observedin women who developed the HELLP syndrome (adjustedOR 41) (Table 2) Combined positivity for any of the TLR-4 and NOD2 allelic variants and high levels of IL-6 were69-fold more common in women with a history of early-onset preeclampsia than in healthy pregnant women (OR69) (Table 2) [52] In women with preeclampsia a persistentTLR-4 signal could reverse the CD4+CD25bright Treg cell-mediated immunosuppression [82]Thismeans that the TLR-4 pathway and the innate immune system might be involved

in development of both theHELLP syndrome and early-onsetpreeclampsia [52]

19 Leptin Gene (LEPR)

During pregnancy hormonal readjustment leads to increasedleptin transcription Women with preeclampsia display sig-nificantly higher serum leptin levels than healthy pregnantwomen High leptin levels correlated with the blood pressurevalues [53] Chronic hyperlipemia was associated with anincreased release of the vasoconstrictor endothelin as well asan activation of the sympatric nerve system which may causevasoconstriction [83]

The leptin receptor (LEPR) is a member of the superfamily of cytokine receptors The LEPR gene is transcribedin the villous and EVTs Its serum level correlates with theleptin concentration in peripheral blood [84]The leptin genepolymorphisms were examined in women with preeclampsia(119899 = 40) and in control women (119899 = 29) by Muy-Riveraet al [73] Maternal plasma leptin and SLR concentrationswere measured using enzyme immunoassays (DiagnosticSystems Laboratory Inc Webster Texas USA) Elevatedleptin concentrations (145 ngmL) were associated with a38-fold increased risk of preeclampsia (OR 38) (Table 2)whereas low soluble leptin receptor (SLR) (lt285 ngmL) wasassociated with a 63-fold increased risk of preeclampsia 63-fold (OR 63 95CI 17ndash232) On the other hand the IIIgenotype was associated with a 38-fold increased risk ofpreeclampsia (OR 38) (Table 2) [73]

The frequency of LEPR 223AA genotype in women withsevere preeclampsia (119899 = 24) and healthy pregnant women(119899 = 107) was analysed by Rigo Jr et al Peripheral bloodsamples taken for routine laboratory investigations wereused for genotyping the two common DNA sequence vari-ants in exons 4 and 6 of the LEPR gene using the PCR restric-tion fragment length polymorphism (RFLP) Genomic DNAwas extracted using the standard phenol-chloroform extrac-tion procedure [54] Women with the LEPR 223G allele(223AG or 223GG genotype) had almost a doubled risk ofdeveloping severe preeclampsia compared with women withthe 223AA genotype (adjusted OR 192) (Table 2) [54]Thusthe LEPR gene is associated with increased risk of developingpreeclampsia

20 MicroRNA (MiRNA)

MiRNAs are noncoding 20ndash30 bp nucleotide RNAs with neg-ative regulation functions which control the gene expressionby binding to messenger RNAs and play roles in biologicalfunctions like cell proliferation differentiation apoptosiscardiovascular disease and carcinogenesis [85 86] TheMiRNAs are abundantly expressed in the placenta Zhu et alfound several microRNA clusters on chromosomes 19q134213q313 Xq262 Xq263 and 14q3231 (a human imprintedregion) which were expressed differentially in the placentaof women with preeclampsia The results showed that inwomen with preeclampsia microRNAs were deregulatedsuggesting involvement of microRNAs in the pathogenesis[87]


21 Chorionic Villous Samples (CVS) andDeregulation of Placental Genes

The human placenta is prerequisite for the development ofpreeclampsia and the HELLP syndrome Several studies havefocused on placental genes Farina et al analysed chorionicvillous samples (CVS) from the 11th gestational week fromwomen who developed preeclampsia (119899 = 10) and healthycontrols (119899 = 50) with microarray Altered expression wasfound among several genes including those involved in inva-sion of EVT (Titin) in inflammatory stress (Lactotransferrin)endothelial aberration (Claudin 6) angiogenesis (Vasohibin1) and blood pressure control (Adducin 1) CVS showed anaberrant gene profile prior to development of preeclampsia[88] Founds et al performed 160 CVS at 10ndash12-week gesta-tion Thirty-six differentially expressed genes were identifiedin the preeclampsia placenta Decidual gene deregulation wasprominent [89]

22 Microarray Study ofWomen with Early-Onset Preeclampsiaand the HELLP Syndrome

Varkonyi et al conducted a microarray study of womenwith early-onset preeclampsia and women with the HELLPsyndrome Placental specimens were obtained by Cesareansections from women with early-onset preeclampsia andwomenwith theHELLP syndrome Placental specimens werecollected after birth from control women who delivered vagi-nally preterm or at term After histopathological examina-tion fresh-frozen placental specimenswere used formicroar-ray profiling and validation by quantitative real-time PCROut of the 350 differentially expressed genes in women withpreeclampsia and 554 genes in women with the HELLPsyndrome 224 genes (including LEP CGB LHB INHASIGLEC6 PAPPA2 TREM1 and FLT1) changed in the samedirection (elevated or reduced) in both syndromes Enrich-ment analyses revealed similar biological processes cellularcompartments and biological pathways enriched in early-onset preeclampsia and the HELLP syndrome Howeversome processes and pathways (eg cytokine-cytokine recep-tor interaction) were overrepresented in women with theHELLP syndrome [90]

In accordance with the altered trophoblast pathophysi-ology in early-onset preeclampsia many of the most differ-entially regulated genes in women with preeclampsia (LEPCGB LHB INHA SIGLEC6 PAPPA2 and FLT1) have pre-dominant or unique expression in the syncytiotrophoblasts[91]The results of the study by Varkonyi et al may imply thattrophoblastic metabolic signals overactivated the reproduc-tive axis in womenwith early-onset preeclampsia andwomenwith the HELLP syndrome Moreover enrichment analysesalso revealed the overrepresentation of biological processesmolecular functions and pathways that are related to utero-placental vascular insufficiency and placental oxidative stressknown to play key roles in the pathophysiology of early-onsetpreeclampsia [8 21 92]

23 Discussion and Future Directions

The present review highlights several of the genetic factorsplaying roles in development of preeclampsia and the HELLPsyndrome A variety of genes are involved which also inter-act The mechanisms are very complicated Gene variantsin the Fas receptor the VEGF gene and the coagulationfactor V Leiden mutation are associated with increasedrisk of the HELLP syndrome compared to healthy women[51 69 77] Variants in the Bell polymorphism [93] andthe TLR-4 increased the risk of HELLP significantly morethan the risk of preeclampsia [52] A weakness of ourpublication is that it is an unsystematic review carrying riskof missing important references A weakness of many ofthe studies is the low number of cases which makes thegenetic evaluation less certain In addition different criteriahave been used in the diagnosis of preeclampsia and theHELLP syndrome Criteria for incusing and exclusions alsodiffer in evaluating case-control studies of thrombophilia[70]

Interestingly overall gestational age at deliverywas earlierin the studies in which higher ORs were reported which mayimply a more severe preeclampsia For example the casesof preeclampsia reported by Scholz et al were delivered atless than 28 weeks In this group the factor V Leiden OR forpreeclampsia was 57 [44] In contrast the cases reported byDe Groot et al which were delivered at 34-week gestationno association between preeclampsia and factor V Leidenmutation was observed [94]

Retrospective studies suggest that the heritable allelicvariations particularly the uteroplacental renin-angiotensinsystem with defective placental vascular development couldbecome the cornerstone for the genetics of preeclampsia[74]

In a study it was shown that decidual dendritic cells (DC)stained and reacted differently with decidual natural killer(dNK) cells in women with the HELLP syndrome com-pared to women with preeclampsia [44] In another studyapoptosis proliferation and FasL expression were higherin villous trophoblast in women with the HELLP syndromethan in the women with preeclampsia and the control groupPlacentas from a preeclampsia group had higher levels ofapoptosis lower FasL expression and no difference in pro-liferation compared with the control group The findings inthis study suggested different pathophysiologic mechanismsin development of preeclampsia and the HELLP syndrome[95]

In the future there is a need of multicenter studies witha large number of cases using the latest technology suchas array comparative genomic hybridization and massiveparallel sequencing to reveal the genetic changes which haveoccurred on the whole genome in women with preeclampsiaand the HELLP syndrome The microarrays with a highnumber of SNPs also seem promisingThe use of free nucleicacids is still at the early stage More studies are needed also toapply DNA RNA and miRNA measurements It is possiblethat amassive parallel sequencingmight contribute to a betterunderstanding of the pathophysiology of preeclampsia andthe HELLP syndrome


Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

References

[1] G A Dekker and B M Sibai ldquoEtiology and pathogenesis ofpreeclampsia current conceptsrdquo American Journal of Obstetricsand Gynecology vol 179 no 5 pp 1359ndash1375 1998

[2] N Sagen O Koller and K Haram ldquoHaemoconcentration insevere pre-eclampsiardquo British Journal of Obstetrics and Gynae-cology vol 89 no 10 pp 802ndash805 1982

[3] B Sibai G Dekker and M Kupferminc ldquoPre-eclampsiardquo TheLancet vol 365 no 9461 pp 785ndash799 2005

[4] K Haram E Svendsen and U Abildgaard ldquoThe HELLP syn-drome clinical issues and management A reviewrdquo BMC Preg-nancy and Childbirth vol 9 article 8 2009

[5] J M Roberts and C A Hubel ldquoThe two stage model of pree-clampsia variations on the themerdquo Placenta vol 30 pp 32ndash372009

[6] B Franzas ldquoHydatidiform mole and pre-eclampsiardquo AnnalesChirurgiae et Gynaecologiae Fenniae vol 47 no 81 pp 11ndash161958

[7] A M Borzychowski I L Sargent and C W G RedmanldquoInflammation and pre-eclampsiardquo Seminars in Fetal andNeonatal Medicine vol 11 no 5 pp 309ndash316 2006

[8] CWRedman and I L Sargent ldquoLatest advances in understand-ing preeclampsiardquo Science vol 308 no 5728 pp 1592ndash15942005

[9] J N Martin Jr C H Rose and C M Briery ldquoUnderstandingand managing HELLP syndrome the integral role of aggressiveglucocorticoids for mother and childrdquo American Journal ofObstetrics and Gynecology vol 195 no 4 pp 914ndash934 2006

[10] C B M Oudejans and M van Dijk ldquoPlacental gene expressionand pre-eclampsiardquo Placenta vol 29 pp 78ndash82 2008

[11] U Abildgaard and K Heimdal ldquoPathogenesis of the syndromeof hemolysis elevated liver enzymes and low platelet count(HELLP) a reviewrdquo European Journal of Obstetrics and Gyne-cology and Reproductive Biology vol 166 pp 117ndash123 2013

[12] S Sep L Smits M Prins and L Peeters ldquoPrediction testsfor recurrent hypertensive disease in pregnancy a systematicreviewrdquo Hypertension in Pregnancy vol 29 no 2 pp 206ndash2302010

[13] K E Fitzpatrick K Hinshaw J J Kurinczuk and M KnightldquoRisk factors management and outcomes of hemolysis ele-vated liver enzymes and low platelets syndrome and elevatedliver enzymes low platelets syndromerdquo Obstetrics and Gyne-colog vol 123 no 3 pp 618ndash627 2014

[14] GDekker P Y Robillard andC Roberts ldquoThe etiology of pree-clampsia the role of the fatherrdquo Journal of Reproductive Immu-nology vol 89 no 2 pp 126ndash132 2011

[15] A F Saftlas L Rubenstein K Prater K K Harland E Fieldand E W Triche ldquoCumulative exposure to paternal seminalfluid prior to conception and subsequent risk of preeclampsiardquoJournal of Reproductive Immunology vol 101-102 pp 104ndash1102014

[16] A F Saftlas R J Levine M A Klebanoff et al ldquoAbortionchanged paternity and risk of preeclampsia in nulliparouswomenrdquo American Journal of Epidemiology vol 157 no 12 pp1108ndash1114 2003

[17] C B M Oudejans M Dijk M Oosterkamp A Lachmeijerand M A Blankenstein ldquoGenetics of preeclampsia paradigmshiftsrdquo Human Genetics vol 120 no 5 pp 607ndash612 2007

[18] J M Roberts and H S Gammill ldquoPreeclampsia recentinsightsrdquo Hypertension vol 46 no 6 pp 1243ndash1249 2005

[19] M W Aardema H Oosterhof A Timmer I van Rooy and JG Aarnoudse ldquoUterine artery Doppler flow and uteroplacentalvascular pathology in normal pregnancies and pregnanciescomplicated by pre-eclampsia and small for gestational agefetusesrdquo Placenta vol 22 no 5 pp 405ndash411 2001

[20] J M Roberts and C A Hubel ldquoIs oxidative stress the link inthe two-stagemodel of pre-eclampsiardquoTheLancet vol 354 no9181 pp 788ndash789 1999

[21] J M Roberts and K Y Lain ldquoRecent insights into the patho-genesis of pre-eclampsiardquo Placenta vol 23 no 5 pp 359ndash3722002

[22] J M Roberts and C A Hubel ldquoThe two stage model of pree-clampsia variations on the themerdquo Placenta vol 30 pp S32ndashS37 2009

[23] M Buimer R Keijser J M Jebbink et al ldquoSeven placentaltranscripts characterize HELLP-syndromerdquo Placenta vol 29no 5 pp 444ndash453 2008

[24] JM Roberts ldquoPreeclampsia what we know andwhat we do notknowrdquo Seminars in Perinatology vol 24 no 1 pp 24ndash28 2000

[25] B Huppertz ldquoPlacental origins of preeclampsia challenging thecurrent hypothesisrdquo Hypertension vol 51 no 4 pp 970ndash9752008

[26] B M Sibai ldquoThe HELLP syndrome (hemolysis elevated liverenzymes and low platelets) much ado about nothingrdquo Ameri-can Journal of Obstetrics and Gynecology vol 162 no 2 pp 311ndash316 1990

[27] S Chappell and L Morgan ldquoSearching for genetic clues to thecauses of pre-eclampsiardquo Clinical Science vol 110 no 4 pp443ndash458 2006

[28] R T Lie S Rasmussen H Brunborg H K Gjessing E Lie-Nielsen and L M Irgens ldquoFetal and maternal contributions torisk of pre-eclampsia population based studyrdquo British MedicalJournal vol 316 no 7141 pp 1343ndash1347 1998

[29] R Skjaeligrven L J Vatten A J Wilcox T Roslashnning L MIrgens and R T Lie ldquoRecurrence of pre-eclampsia across gene-rations exploring fetal and maternal genetic components in apopulation based cohortrdquo British Medical Journal vol 331 no7521 pp 877ndash879 2005

[30] TMorgan and KWard ldquoNew insights into the genetics of pree-clampsiardquo Seminars in Perinatology vol 23 no 1 pp 14ndash231999

[31] S Cnattingius M Reilly Y Pawitan and P Lichtenstein ldquoMat-ernal and fetal genetic factors account formost of familial aggre-gation of preeclampsia a population-based swedish cohortstudyrdquo American Journal of Medical Genetics vol 130 no 4 pp365ndash371 2004

[32] R H Salonen P Lichtenstein L Lipworth and S CnattingiusldquoGenetic effects on the liability of developing pre-eclampsiaand gestational hypertensionrdquo American Journal of MedicalGenetics vol 91 no 4 pp 256ndash260 2000

[33] MHabli N Eftekhari EWiebracht et al ldquoLong-termmaternaland subsequent pregnancy outcomes 5 years after hemolysiselevated liver enzymes and low platelets (HELLP) syndromerdquoAmerican Journal of Obstetrics and Gynecology vol 201 no 4pp 385e1ndash385e5 2009


[34] P Hupuczi B Rigo I Sziller G Szabo Z Szigeti and Z PappldquoFollow-up analysis of pregnancies complicated by HELLPsyndromerdquo Fetal Diagnosis and Therapy vol 21 no 6 pp 519ndash522 2006

[35] A M A Lachmeijer R Arngrımsson E J Bastiaans et al ldquoAgenome-wide scan for preeclampsia in the Netherlandsrdquo Euro-pean Journal ofHumanGenetics vol 9 no 10 pp 758ndash764 2001

[36] R Arngrımsson S Siguroardottir M L Frigge et al ldquoA gen-ome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13rdquo Human Molecular Geneticsvol 8 no 9 pp 1799ndash1805 1999

[37] M P Johnson L T Roten T D Dyer et al ldquoThe ERAP2 geneis associated with preeclampsia in Australian and Norwegianpopulationsrdquo Human Genetics vol 126 no 5 pp 655ndash6662009

[38] L T RotenM P Johnson S Forsmo et al ldquoAssociation betweenthe candidate susceptibility gene ACVR2A on chromosome2q22 and pre-eclampsia in a large Norwegian population-basedstudy (theHUNT study)rdquo European Journal of HumanGeneticsvol 17 no 2 pp 250ndash257 2009

[39] K A B Goddard G Tromp R Romero et al ldquoCandidate-gene association study ofmothers with pre-eclampsia and theirinfants analyzing 775 SNPs in 190 genesrdquoHuman Heredity vol63 no 1 pp 1ndash16 2007

[40] J-L Frendo D Olivier V Cheynet et al ldquoDirect involvementof HERV-W Env glycoprotein in human trophoblast cell fusionand differentiationrdquoMolecular and Cellular Biology vol 23 no10 pp 3566ndash3574 2003

[41] G J BurtonD S Charnock-Jones andE Jauniaux ldquoRegulationof vascular growth and function in the human placentardquo Repro-duction vol 138 no 6 pp 895ndash902 2009

[42] D S Goldman-Wohl and S Yagel ldquoExamination of distinct fetalandmaternal molecular pathways suggests amechanism for thedevelopment of preeclampsiardquo Journal of Reproductive Immu-nology vol 76 no 1-2 pp 54ndash60 2007

[43] B Nagy P Hupuczi and Z Papp ldquoHigh frequency of methyl-enetetrahydrofolate reductase 677TT genotype in HungarianHELLP syndrome patients determined by quantitative real-time PCRrdquo Journal of Human Hypertension vol 21 no 2 pp154ndash158 2007

[44] C Scholz B Toth L Santoso et al ldquoDistribution and maturityof dendritic cells in diseases of insufficient placentationrdquo Amer-ican Journal of Reproductive Immunology vol 60 no 3 pp 238ndash245 2008

[45] C Benedetto L Marozio L Salton V Maula G Chieppa andM Massobrio ldquoFactor V Leiden and factor II G20210A in pree-clampsia and HELLP syndromerdquoActa Obstetricia et Gynecolog-ica Scandinavica vol 81 no 12 pp 1095ndash1100 2002

[46] S Weed J A Bastek L Anton M A Elovitz S Parry and SK Srinivas ldquoExamining the correlation between placental andserum placenta growth factor in preeclampsiardquo American Jour-nal of Obstetrics and Gynecology vol 207 no 2 pp 140ndash1462012

[47] V Vincenti C Cassano M Rocchi and M G Persico ldquoAssign-ment of the vascular endothelial growth factor gene to humanchromosome 6p213rdquo Circulation vol 93 no 8 pp 1493ndash14951996

[48] C L D de Jong G A Dekker and BM Sibai ldquoThe renin-angi-otensin-aldosterone system in preeclampsia a reviewrdquoClinics inPerinatology vol 18 no 4 pp 683ndash711 1991

[49] P LM ZusterzeelWHM PetersWVisser K JMHermsenH M J Roelofs and E A P Steegers ldquoA polymorphism in the

gene for microsomal epoxide hydrolase is associated with pre-eclampsiardquo Journal of Medical Genetics vol 38 no 4 pp 234ndash237 2001

[50] SW Kauma T F Huff NHayes andANilkaeo ldquoPlacental Fasligand expression is a mechanism for maternal immune tole-rance to the fetusrdquo Journal of Clinical Endocrinology and Meta-bolism vol 84 no 6 pp 2188ndash2194 1999

[51] I Sziller P Hupuczi N Normand A Halmos Z Papp andS S Witkin ldquoFas (TNFRSF6) gene polymorphism in pregnantwomen with hemolysis elevated liver enzymes and low plate-lets and in their neonatesrdquo Obstetrics and Gynecology vol 107no 3 pp 582ndash587 2006

[52] B B van Rijn A Franx E A P Steegers et al ldquoMaternalTLR4 and NOD2 gene variants pro-inflammatory phenotypeand susceptibility to early-onset preeclampsia and HELLP syn-dromerdquo PLoS ONE vol 3 no 4 Article ID e1865 2008

[53] N Anim-Nyame S R Sooranna P J Steer and M R JohnsonldquoLongitudinal analysis of maternal plasma leptin concentra-tions during normal pregnancy and pre-eclampsiardquo HumanReproduction vol 15 no 9 pp 2033ndash2036 2000

[54] J Rigo Jr G Szendei K Rosta et al ldquoLeptin receptor genepolymorphisms in severely pre-eclamptic womenrdquo Gynecolog-ical Endocrinology vol 22 no 9 pp 521ndash525 2006

[55] M van Dijk S Drewlo and C B M Oudejans ldquoDifferentialmethylation of STOX1 in human placentardquo Epigenetics vol 5no 8 pp 736ndash742 2010

[56] A L Berends A M Bertoli-Avella C J M de Groot C M vanDuijn B A Oostra and E A P Steegers ldquoSTOX1 gene in pre-eclampsia and intrauterine growth restrictionrdquo BJOG vol 114no 9 pp 1163ndash1167 2007

[57] I Iglesias-Platas D Monk J Jebbink et al ldquoSTOX1 is notimprinted and is not likely to be involved in preeclampsiardquoNature Genetics vol 39 no 3 pp 279ndash280 2007

[58] KKivinenH Peterson LHiltunen et al ldquoEvaluation of STOX1as a preeclampsia candidate gene in a population-wide samplerdquoEuropean Journal of Human Genetics vol 15 no 4 pp 494ndash4972007

[59] V Rigourd C Chauvet S T Chelbi et al ldquoSTOX1 overexpres-sion in choriocarcinoma cellsmimics transcriptional alterationsobserved in preeclamptic placentasrdquo PLoS ONE vol 3 no 12Article ID e3905 2008

[60] M van Dijk J van Bezu D van Abel et al ldquoThe STOX1 geno-type associated with pre-eclampsia leads to a reduction of tro-phoblast invasion by 120572-T-catenin upregulationrdquoHumanMolec-ular Genetics vol 19 no 13 pp 2658ndash2667 2010

[61] M van Dijk and C B M Oudejans ldquoSTOX1 key player introphoblast dysfunction underlying early onset preeclampsiawith growth retardationrdquo Journal of Pregnancy vol 2011 ArticleID 521826 7 pages 2011

[62] J-L Blond D Lavillette V Cheynet et al ldquoAn envelopeglycoprotein of the human endogenous retrovirus HERV-W isexpressed in the human placenta and fuses cells expressing thetype Dmammalian retrovirus receptorrdquo Journal of Virology vol74 no 7 pp 3321ndash3329 2000

[63] M Sha X Lee X-P Li et al ldquoSyncytin is a captive retroviralenvelope protein involved in human placental morphogenesisrdquoNature vol 403 no 6771 pp 785ndash789 2000

[64] N G Than O Abdul Rahman R Magenheim et al ldquoPlacentalprotein 13 (galectin-13) has decreased placental expression butincreased shedding and maternal serum concentrations inpatients presenting with preterm pre-eclampsia and HELLPsyndromerdquo Virchows Archiv vol 453 no 4 pp 387ndash400 2008


[65] I Knerr E Beinder and W Rascher ldquoSyncytin a novel humanendogenous retroviral gene in human placenta evidence for itsdysregulation in preeclampsia and HELLP syndromerdquo Ameri-can Journal of Obstetrics and Gynecology vol 186 no 2 pp 210ndash213 2002

[66] M Langbein R Strick P L Strissel et al ldquoImpaired cytotro-phoblast cell-cell fusion is associated with reduced syncytinand increased apoptosis in patients with placental dysfunctionrdquoMolecular Reproduction andDevelopment vol 75 no 1 pp 175ndash183 2008

[67] I Sziller O Babula P Hupuczi et al ldquoMannose-binding lectin(MBL) codon 54 gene polymorphism protects against develop-ment of pre-eclampsia HELLP syndrome and pre-eclampsia-associated intrauterine growth restrictionrdquo Molecular HumanReproduction vol 13 no 4 pp 281ndash285 2007

[68] J Lin andPAugust ldquoGenetic thrombophilias and preeclampsiaa meta-analysisrdquo Obstetrics and Gynecology vol 105 no 1 pp182ndash192 2005

[69] S Muetze B Leeners J R Ortlepp et al ldquoMaternal factor VLeiden mutation is associated with HELLP syndrome in Cau-casian womenrdquo Acta Obstetricia et Gynecologica Scandinavicavol 87 no 6 pp 635ndash642 2008


[71] J Lin andPAugust ldquoGenetic thrombophilias and preeclampsiaa meta-analysisrdquo Obstetrics amp Gynecology vol 105 no 1 pp182ndash192 2005

[72] E Sgambati M Marini G D Zappoli Thyrion et al ldquoVEGFexpression in the placenta from pregnancies complicated byhypertensive disordersrdquoBJOG vol 111 no 6 pp 564ndash570 2004

[73] M Muy-Rivera Y Ning I O Frederick S Vadachkoria DA Luthy and M A Williams ldquoLeptin soluble leptin receptorand leptin gene polymorphism in relation to preeclampsia riskrdquoPhysiological Research vol 54 no 2 pp 167ndash174 2005

[74] A Perez-Sepulveda P P Espana-Perrot X B Fernandez etal ldquoLevels of key enzymes of methionine-homocysteine meta-bolism in preeclampsiardquo BioMed Research International vol2013 Article ID 731962 8 pages 2013

[75] S R Poort F R Rosendaal P H Reitsma and R M BertinaldquoA common genetic variation in the 31015840-untranslated region ofthe prothrombin gene is associated with elevated plasma pro-thrombin levels and an increase in venous thrombosisrdquo Bloodvol 88 no 10 pp 3698ndash3703 1996

[76] M J Kupferminc A Eldor N Steinman et al ldquoIncreased fre-quency of genetic thrombophilia in women with complicationsof pregnancyrdquo The New England Journal of Medicine vol 340no 1 pp 9ndash13 1999

[77] B Nagy H Savli A Molvarec et al ldquoVascular endothelialgrowth factor (VEGF) polymorphisms in HELLP syndromepatients determined by quantitative real-time PCR and meltingcurve analysesrdquo Clinica Chimica Acta vol 389 no 1-2 pp 126ndash131 2008

[78] G G Zeeman andG A Dekker ldquoPathogenesis of preeclampsiaa hypothesisrdquo Clinical Obstetrics and Gynecology vol 35 no 2pp 317ndash337 1992

[79] G Mello E Parretti F Gensini et al ldquoMaternal-fetal flow neg-ative events and preeclampsia role of ACE ID polymorphismrdquoHypertension vol 41 no 4 pp 932ndash937 2003

[80] R Bertalan A Patocs B Nagy et al ldquoOverrepresentationof BclI polymorphism of the glucocorticoid receptor gene inpregnantwomenwithHELLP syndromerdquoClinicaChimicaActavol 405 no 1-2 pp 148ndash152 2009

[81] M K Yeon R Romero Y O Seo et al ldquoToll-like receptor 4a potential link between ldquodanger signalsrdquo the innate immunesystem and preeclampsiardquo American Journal of Obstetrics andGynecology vol 193 supplement 3 pp 921e1ndash921e8 2005

[82] Y Sasaki D Darmochwal-Kolarz D Suzuki et al ldquoProportionof peripheral blood and decidual CD4+ CD25bright regulatory Tcells in pre-eclampsiardquo Clinical and Experimental Immunologyvol 149 no 1 pp 139ndash145 2007

[83] J Bełtowski ldquoRole of leptin in blood pressure regulation andarterial hypertensionrdquo Journal of Hypertension vol 24 no 5 pp789ndash801 2006

[84] M C Henson K F Swan and J S OrsquoNeil ldquoExpression ofplacental leptin and leptin receptor transcripts in early preg-nancy and at termrdquo Obstetrics and Gynecology vol 92 no 6pp 1020ndash1028 1998

[85] N Bushati and S M Cohen ldquoMicroRNA functionsrdquo AnnualReview of Cell and Developmental Biology vol 23 pp 175ndash2052007

[86] I Eisenberg A Eran I Nishino et al ldquoDistinctive patterns ofmicroRNA expression in primarymuscular disordersrdquo Proceed-ings of the National Academy of Sciences of the United States ofAmerica vol 104 no 43 pp 17016ndash17021 2007

[87] X-M Zhu T Han I L Sargent G-W Yin and Y-Q YaoldquoDifferential expression profile of microRNAs in human pla-centas from preeclamptic pregnancies vs normal pregnanciesrdquoAmerican Journal of Obstetrics and Gynecology vol 200 no 6pp 661e1ndash661e7 2009

[88] A Farina D Morano D Arcelli et al ldquoGene expression inchorionic villous samples at 11 weeks of gestation in womenwho develop preeclampsia later in pregnancy implications forscreeningrdquo Prenatal Diagnosis vol 29 no 11 pp 1038ndash10442009

[89] S A Founds Y P Conley J F Lyons-Weiler A Jeyabalan WAllen Hogge and K P Conrad ldquoAltered global gene expressionin first trimester placentas of women destined to developpreeclampsiardquo Placenta vol 30 no 1 pp 15ndash24 2009

[90] T Varkonyi B Nagy T Fule et al ldquoMicroarray profiling revealsthat placental transcriptomes of early-onset HELLP syndromeand preeclampsia are similarrdquo Placenta vol 32 supplement 1pp S21ndashS29 2011

[91] D Islami P Bischof and D Chardonnens ldquoPossible inter-actions between leptin gonadotrophin-releasing hormone(GnRH-I and II) and human chorionic gonadotrophin (hCG)rdquoEuropean Journal of Obstetrics Gynecology and ReproductiveBiology vol 110 no 2 pp 169ndash175 2003

[92] G J Burton A W Woods E Jauniaux and J C P KingdomldquoRheological and physiological consequences of conversion ofthematernal spiral arteries for uteroplacental blood flow duringhuman pregnancyrdquo Placenta vol 30 no 6 pp 473ndash482 2009

[93] R Bertalan A Patocs B Nagy et al ldquoOverrepresentation ofBclI polymorphism of the glucocorticoid receptor gene in preg-nant womenwithHELLP syndromerdquoClinica Chimica Acta vol405 no 1-2 pp 148ndash152 2009

[94] C J M de Groot K W M Bloemenkamp E J Duvekot et alldquoPreeclampsia and genetic risk factors for thrombosis a case-control studyrdquo American Journal of Obstetrics and Gynecologyvol 181 no 4 pp 975ndash980 1999


[95] I K Prusac S Zekic Tomas and D Roje ldquoApoptosis prolife-ration and Fas ligand expression in placental trophoblastfrom pregnancies complicated by HELLP syndrome or pre-eclampsiardquo Acta Obstetricia et Gynecologica Scandinavica vol90 no 10 pp 1157ndash1163 2011

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


a maternal syndrome with lesions in different organs andvarious clinical symptoms [5]

Preeclampsia may occur without a fetus in the case ofhydatidiform mole [6] It is established that preeclampsiaoriginates in the placenta [3 7 8] It is conceivable that theHELLP syndrome also is a placenta-dependent condition[9 10] Following delivery of the placenta the maternal symp-toms and signs of preeclampsia often disappear but a pro-tracted course of a severe HELLP syndrome is not unusual[11]

A variety of molecular factors are involved in the patho-physiology of preeclampsia and the HELLP syndrome Theaim of this publication is to present a review and a com-prehensive description of the genetic factors involved and tosuggest modes of action in development of preeclampsia andthe HELLP syndrome

2 Search Strategy

An unsystematic search in PubMed was conducted by usingthe search words ldquopreeclampsiardquo or ldquoHELLPrdquo combined withldquoetiologyrdquo or ldquogenerdquo or combined with risk factors respec-tively (2000ndash2013) Abstracts were read and the publicationcited if it was considered adequate

3 Risk Factors for Preeclampsia andthe HELLP Syndrome

Several risk factors have been identified with increased riskof preeclampsia Preeclampsia is generally regarded as adisease of the first pregnancyThe risk factors include chronichypertension renal diseases obesity and insulin resistancediabetes mellitus preexisting thrombophilia family historyof preeclampsia and smoking [3] High body mass index(BMI) and metabolic syndrome 6 months postpartum wereassociated with preeclampsia but hardly with HELLP [12]

Most white womenwithHELLP aremultiparousWomenwith a HELLP syndrome are more likely than those in thecontrol group to be gt35 years old (33 compared with22) be nulliparous (67 compared with 43) have hada previous gestational hypertensive disorder (9 comparedwith 7) and have a multiple pregnancy (7 compared with2) [13]

The risk of preeclampsia increases in those who havelimited sperm exposure with the same partner before con-ceptionMost epidemiologic studies demonstrate that regularsexual intercourse of an extended period reduces the risk[14 15] Women with a history of abortion who conceivedagain with the same partner had nearly half the risk ofpreeclampsia compared to women without a history of abor-tion In contrast women with an abortion history who con-ceived with a new partner had the same risk as womenwithout a history of abortion [16]

31 The ldquoRoot Causerdquo Preeclampsia and the HELLP syn-drome both originate in the placenta [17] The ldquoroot causerdquoof preeclampsia is thought to be reduced placental perfusion[18] It has been demonstrated that impaired extra villoustrophoblasts (EVTs) invasion in the decidua and the spiral

arteries and insufficient spiral artery remodeling may takeplace both in women with preeclampsia and in women with aHELLP syndrome [19] Reduced placental perfusion interactswith preexisting maternal disorders such as hypertensionrenal disease overweight diabetes mellitus obesity lipidabnormalities and insulin resistance This will affect thematernal susceptibility to preeclampsia because it liberatesbioactive factors which pass through the intervillous spaceinto thematernal circulation inducing an inflammatory reac-tion and endothelial dysfunction [20ndash22]

HELLP and preeclampsia become clinically manifestduring the second (early-onset form) or third trimester (late-onset form) of pregnancy but the initiating event occursmuch earlier in gestation [23] The resultant symptomaticsecond stage of preeclampsia thematernal syndrome usuallydevelops after the 20th gestational week [8 24] The HELLPsyndrome is also associated with widespread organ damagewith different clinical signs in the second stage [4 10]

However implantation disorders can be detected in thefirst trimester before 12 to 20 weeksrsquo gestation when the deepinvasion of EVT and spiral artery remodeling occur and priorto failed vascular remodeling of the spiral arteries necessaryto reduce placental perfusion [22 25] In some cases ofpreeclampsia and a HELLP syndrome aberrant restructuringof the uterine spiral arteries by invading trophoblasts betweenweeks 8 and 12 of gestation ultimately causes poor placentalperfusion and placental ischemia [26] Thus factors whichincrease the risk of preeclampsia and are associated withabnormal implantation in early pregnancymight be the ldquorealrdquoldquoroot causerdquo of preeclampsia [22 25]

4 Genetic Considerations

41 Epidemiologic Studies It has been recognised for manyyears that preeclampsia has different genetic components[27] Both maternal and fetal genes appear to play etiolog-ical roles Evidence for a role for paternally inherited fetalgenomes comes from an analysis of data from the NorwegianMedical Birth Registry from 1967 to 1992 which identifiedalmost 400000womenwho had had at least two pregnanciesIt was possible from the records to distinguish between apregnancy with the same parents and those where themotheror the father differed in the second pregnancy [28] In the firstpregnancies the risk of preeclampsia was above 3 slightlyincreasingwithmotherrsquos ageThe riskwas 17 among secondpregnancies inmothers who had their second pregnancywiththe same partner and 19 among second pregnancies inmothers who had changed their partner since the first preg-nancy [28] Men who were born from a preeclampsia preg-nancywere at risk of fathering a preeclampsia pregnancy [29]First degree female relatives of womenwith preeclampsia hada 5-fold higher risk and seconddegree relatives a 2-fold higherrisk of developing preeclampsia thanwomenwithout a familyhistory of preeclampsia [30] Studies of familial aggregationof preeclampsia indicate that genetic factors may contributemore than 50 of the variability in liability to preeclampsia[31 32]

Women with a history of HELLP are at increased riskof preeclampsia (22ndash28) and a HELLP syndrome (14ndash24)



5 Candidate Genes









7 The STOX1 Gene







[41]


[42]






[48]



[49]



[50]



[51]



[52]


[53]


[54]




























[45]




(151ndash608)[72]


[72]


(145ndash574)[49]



































20 MicroRNA (MiRNA)

















References









































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















5 Candidate Genes









7 The STOX1 Gene







[41]


[42]






[48]



[49]



[50]



[51]



[52]


[53]


[54]




























[45]




(151ndash608)[72]


[72]


(145ndash574)[49]



































20 MicroRNA (MiRNA)

















References









































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















[41]


[42]






[48]



[49]



[50]



[51]



[52]


[53]


[54]




























[45]




(151ndash608)[72]


[72]


(145ndash574)[49]



































20 MicroRNA (MiRNA)

















References









































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































[45]




(151ndash608)[72]


[72]


(145ndash574)[49]



































20 MicroRNA (MiRNA)

















References









































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





































20 MicroRNA (MiRNA)

















References









































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of































References









































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of























































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Genetic Aspects of Preeclampsia and the HELLP Syndrome · the HELLP syndrome and...

Documents

Transcript of Review Article Genetic Aspects of Preeclampsia and the HELLP Syndrome · the HELLP syndrome and...