{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,8]],"date-time":"2025-07-08T13:32:18Z","timestamp":1751981538299},"reference-count":42,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,2,16]],"date-time":"2016-02-16T00:00:00Z","timestamp":1455580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2016,4]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>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 (<jats:italic>MTHFR<\/jats:italic>) gene, we hypothesize that a gene\u2013environment interaction between this polymorphism and folic acid use is involved in the etiology of hypospadias.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a case\u2013control study among 855 hypospadias cases and 713 population\u2010based controls from the AGORA data\u2010 and biobank. Folic acid supplement use was derived from maternal questionnaires and infant and maternal DNA was used to determine the <jats:italic>MTHFR<\/jats:italic> C677T polymorphism using Taqman assays. We performed separate analyses for different hypospadias phenotypes (anterior\/middle\/posterior).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Hypospadias was neither associated with folic acid use or the <jats:italic>MTHFR<\/jats:italic> 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\u20132.4), especially in infants carrying the CT\/TT genotype (odds ratio = 2.5; 95% confidence interval, 1.4\u20134.7). In addition, more infants with these genotypes seemed to have posterior hypospadias, regardless of folic acid use.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study does not suggest a major role for folic acid supplements or the <jats:italic>MTHFR<\/jats:italic> C677T polymorphism in the etiology of hypospadias in general, but not using folic acid and\/or carrying the <jats:italic>MTHFR<\/jats:italic> C677T polymorphism may be associated with middle and posterior hypospadias. Therefore, we stress the importance of studying gene\u2013environment interactions preferably in stratified analyses for different hypospadias phenotypes. <jats:italic>Birth Defects Research (Part A) 106:275\u2013284, 2016<\/jats:italic>. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.23487","type":"journal-article","created":{"date-parts":[[2016,2,16]],"date-time":"2016-02-16T08:57:36Z","timestamp":1455613056000},"page":"275-284","source":"Crossref","is-referenced-by-count":5,"title":["Interaction between <i>MTHFR<\/i> 677C&gt;T and periconceptional folic acid supplementation in the risk of Hypospadias"],"prefix":"10.1002","volume":"106","author":[{"given":"Elisabeth M.J.","family":"Dokter","sequence":"first","affiliation":[{"name":"Radboud Institute for Health Sciences, Department for Health Evidence Radboud University Medical Center Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris A.L.M.","family":"van Rooij","sequence":"additional","affiliation":[{"name":"Radboud Institute for Health Sciences, Department for Health Evidence Radboud University Medical Center Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte H.W.","family":"Wijers","sequence":"additional","affiliation":[{"name":"Radboud Institute for Health Sciences, Department for Health Evidence Radboud University Medical Center Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanne M.","family":"Groothuismink","sequence":"additional","affiliation":[{"name":"Radboud Institute for Health Sciences, Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan Jaap","family":"van der Biezen","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery and Hand Surgery Medical Centre Leeuwarden Leeuwarden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wout F.J.","family":"Feitz","sequence":"additional","affiliation":[{"name":"Department of Urology, Paediatric Urology Radboudumc Amalia Children's Hospital Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nel","family":"Roeleveld","sequence":"additional","affiliation":[{"name":"Radboud Institute for Health Sciences, Department for Health Evidence Radboud University Medical Center Nijmegen The Netherlands"},{"name":"Department of Paediatrics Radboudumc Amalia Children's Hospital Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loes F.M.","family":"van der Zanden","sequence":"additional","affiliation":[{"name":"Radboud Institute for Health Sciences, Department for Health Evidence Radboud University Medical Center Nijmegen The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,2,16]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.20547"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10654-005-7835-x"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(05)67861-5"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00345-015-1507-6"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a010291"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a010290"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-006-0304-z"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-410X.2009.08772.x"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2008.74"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2008.09.041"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.306.6893.1645"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19960315)62:2<179::AID-AJMG12>3.0.CO;2-L"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20086"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0595-111"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3063"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.23296"},{"key":"e_1_2_5_18_1","unstructured":"HadidiAT AzmyA.2004.Hypospadias surgery. 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