Interaction between MTHFR 677C>T and periconceptional folic acid supplementation in the risk of Hypospadias
SourceBirth Defects Research Part A-Clinical and Molecular Teratology, 106, 4, (2016), pp. 275-284
Article / Letter to editor
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Birth Defects Research Part A-Clinical and Molecular Teratology
SubjectRadboudumc 10: Reconstructive and regenerative medicine RIHS: Radboud Institute for Health Sciences; Radboudumc 10: Reconstructive and regenerative medicine RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 11: Renal disorders RIHS: Radboud Institute for Health Sciences; Radboudumc 5: Inflammatory diseases RIHS: Radboud Institute for Health Sciences; Radboudumc 6: Metabolic Disorders RIHS: Radboud Institute for Health Sciences
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. CONCLUSION: 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. Birth Defects Research (Part A) 106:275-284, 2016. (c) 2016 Wiley Periodicals, Inc.
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