title: Exploration of gene-environment interactions, maternal effects and parent of origin effects in the etiology of hypospadias.
abstract: OBJECTIVE
  Hypospadias is a common congenital malformation of the male external genitalia. Association studies for single nucleotide polymorphisms in genes encoding steroid 5alpha-reductase, estrogen receptors 1 and 2, and activating transcription factor 3 have been equivocal. We examined whether nonreplication of findings for 4 single nucleotide polymorphisms in these genes could be due to interaction with environmental exposures.
  
  
  METHODS
  We genotyped 712 Dutch hypospadias case-parent triads for the 4 single nucleotide polymorphisms, used questionnaire information to determine exposures and performed association tests using the log-linear approach. We studied gene-environment interactions for the 4 single nucleotide polymorphisms with exposure to estrogens, cytokines or cigarette smoke, multiple birth, being born small for gestational age, maternal hypertension or preeclampsia, high body mass index or primiparity. In addition, the presence of maternal genetic and parent of origin effects was tested.
  
  
  RESULTS
  Gene-environment interactions were identified for rs523349 in SRD5A2 with estrogen exposure and maternal hypertension or preeclampsia, as well as for rs11119982 in ATF3 with exposure to cytokines. Both single nucleotide polymorphisms seemed to influence hypospadias risk only in exposed cases. For rs6932902 in ESR1 only maternally derived alleles appeared to increase hypospadias risk in offspring.
  
  
  CONCLUSIONS
  Interactions between genetic and environmental factors may help to explain nonreplication in genetic studies of hypospadias.
authors.affiliation: Department of Epidemiology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. L.vanderZanden@ebh.umcn.nl
authors.forename: Loes F M
authors.initials: LF
authors.lastname: van der Zanden
authors.forename: Tessel E
authors.initials: TE
authors.lastname: Galesloot
authors.forename: Wout F J
authors.initials: WF
authors.lastname: Feitz
authors.forename: Marijn M
authors.initials: MM
authors.lastname: Brouwers
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: Barbara
authors.initials: B
authors.lastname: Franke
authors.forename: Nel
authors.initials: N
authors.lastname: Roeleveld
authors.forename: Iris A L M
authors.initials: IA
authors.lastname: van Rooij
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics*; D015331:Cohort Studies; D016208:Databases, Factual; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005865:Gestational Age; D006801:Humans; D007021:Hypospadias / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D007231:Infant, Newborn; D016014:Linear Models; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects; D009426:Netherlands; D018812:Paternal Exposure / Q000009:adverse effects; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D012189:Retrospective Studies; D018570:Risk Assessment
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger