title: Interaction between MTHFR 677C>T and periconceptional folic acid supplementation in the risk of Hypospadias.
abstract: BACKGROUND
  Hypospadias is a congenital malformation with both environmental factors and genetic predisposition involved in the pathogenesis. The role of maternal periconceptional folic acid supplement use in the development of hypospadias is unclear. As folate levels may also be influenced by the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, we hypothesize that a gene-environment interaction between this polymorphism and folic acid use is involved in the etiology of hypospadias.
  
  
  METHODS
  We conducted a case-control study among 855 hypospadias cases and 713 population-based controls from the AGORA data- and biobank. Folic acid supplement use was derived from maternal questionnaires and infant and maternal DNA was used to determine the MTHFR C677T polymorphism using Taqman assays. We performed separate analyses for different hypospadias phenotypes (anterior/middle/posterior).
  
  
  RESULTS
  Hypospadias was neither associated with folic acid use or the MTHFR C677T polymorphism, nor with their interaction. However, we did find an association with middle hypospadias when no supplements were used (odds ratio = 1.6; 95% confidence interval, 1.1-2.4), especially in infants carrying the CT/TT genotype (odds ratio = 2.5; 95% confidence interval, 1.4-4.7). In addition, more infants with these genotypes seemed to have posterior hypospadias, regardless of folic acid use.
  
  
  CONCLUSIONS
  Our study does not suggest a major role for folic acid supplements or the MTHFR C677T polymorphism in the etiology of hypospadias in general, but not using folic acid and/or carrying the MTHFR C677T polymorphism may be associated with middle and posterior hypospadias. Therefore, we stress the importance of studying gene-environment interactions preferably in stratified analyses for different hypospadias phenotypes.
authors.affiliation: Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Elisabeth M J
authors.initials: EM
authors.lastname: Dokter
authors.affiliation: Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Iris A L M
authors.initials: IA
authors.lastname: van Rooij
authors.affiliation: Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Charlotte H W
authors.initials: CH
authors.lastname: Wijers
authors.affiliation: Radboud Institute for Health Sciences, Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Johanne M
authors.initials: JM
authors.lastname: Groothuismink
authors.affiliation: Department of Plastic Surgery and Hand Surgery, Medical Centre Leeuwarden, Leeuwarden, The Netherlands.
authors.forename: Jan Jaap
authors.initials: JJ
authors.lastname: van der Biezen
authors.affiliation: Department of Urology, Paediatric Urology, Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands.
authors.forename: Wout F J
authors.initials: WF
authors.lastname: Feitz
authors.affiliation: Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Paediatrics, Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands.
authors.forename: Nel
authors.initials: N
authors.lastname: Roeleveld
authors.affiliation: Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Loes F M
authors.initials: LF
authors.lastname: van der Zanden
mesh_terms: D016022:Case-Control Studies; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage*; D059647:Gene-Environment Interaction; D006801:Humans; D007021:Hypospadias / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: MTHFR; folic acid; gene-environment interaction; hypospadias; multivitamins; pregnancy