PMID- 20215396 OWN - NLM STAT- MEDLINE DCOM- 20100528 LR - 20221207 IS - 1945-7197 (Electronic) IS - 0021-972X (Linking) VI - 95 IP - 5 DP - 2010 May TI - Genetics of hypospadias: are single-nucleotide polymorphisms in SRD5A2, ESR1, ESR2, and ATF3 really associated with the malformation? PG - 2384-90 LID - 10.1210/jc.2009-2101 [doi] AB - CONTEXT: Hypospadias is a common congenital malformation of the male external genitalia with a multifactorial etiology. Little is known about the genes involved in hypospadias. A few genetic associations have been reported but mainly in studies of small sample size. Most of these associations have not been replicated. OBJECTIVE: The aim of this study was to investigate whether previously reported associations for four single-nucleotide polymorphisms (SNPs) in genes involved in hormonal pathways could be replicated in a large Dutch hypospadias sample. The SNPs investigated are rs523349 in steroid-5 alpha-reductase (SRD5A2), rs6932902 in estrogen receptor 1 (ESR1), rs2987983 in ESR2, and rs11119982 in activating transcription factor 3 (ATF3). DESIGN, PARTICIPANTS, AND METHODS: We genotyped 620 Caucasian hypospadias cases and 596 controls for these SNPs using TaqMan-based genotyping. RESULTS: We did not replicate the associations of the SNPs in SRD5A2 and ESR1 with hypospadias. The SNPs in ESR2 and ATF3 were borderline associated with hypospadias [odds ratios 0.9 (95% confidence interval 0.7-1.0) and 1.2 (95% confidence interval 1.0-1.4), respectively] but in the opposite direction compared with earlier publications. Stratification according to localization of the urethral opening produced comparable results in the subgroups. CONCLUSIONS: The lack of consistency between our and previously performed studies might represent spurious results or chance findings in our or the earlier studies, differences in criteria used to select the study populations, or a real difference between populations, i.e. different genes contributing to disease risk. These results once again confirm the importance of replication in genetic association approaches. FAU - van der Zanden, Loes F M AU - van der Zanden LF AD - Department of Epidemiology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. FAU - van Rooij, Iris A L M AU - van Rooij IA FAU - Feitz, Wout F J AU - Feitz WF FAU - Vermeulen, Sita H H M AU - Vermeulen SH FAU - Kiemeney, Lambertus A L M AU - Kiemeney LA FAU - Knoers, Nine V A M AU - Knoers NV FAU - Roeleveld, Nel AU - Roeleveld N FAU - Franke, Barbara AU - Franke B LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20100309 PL - United States TA - J Clin Endocrinol Metab JT - The Journal of clinical endocrinology and metabolism JID - 0375362 RN - 0 (ATF3 protein, human) RN - 0 (Activating Transcription Factor 3) RN - 0 (ESR1 protein, human) RN - 0 (Estrogen Receptor alpha) RN - 0 (Estrogen Receptor beta) RN - 0 (Membrane Proteins) RN - EC 1.3.99.5 (3-Oxo-5-alpha-Steroid 4-Dehydrogenase) RN - EC 1.3.99.5 (SRD5A2 protein, human) SB - IM MH - 3-Oxo-5-alpha-Steroid 4-Dehydrogenase/*genetics MH - Activating Transcription Factor 3/*genetics MH - Child MH - Cryptorchidism/genetics/pathology MH - Estrogen Receptor alpha/*genetics MH - Estrogen Receptor beta/*genetics MH - Genotype MH - Humans MH - Hypospadias/classification/*genetics MH - Male MH - Membrane Proteins/*genetics MH - Netherlands MH - Penis/abnormalities MH - *Polymorphism, Single Nucleotide MH - Retrospective Studies MH - Scrotum/abnormalities MH - White People/genetics EDAT- 2010/03/11 06:00 MHDA- 2010/05/29 06:00 CRDT- 2010/03/11 06:00 PHST- 2010/03/11 06:00 [entrez] PHST- 2010/03/11 06:00 [pubmed] PHST- 2010/05/29 06:00 [medline] AID - jc.2009-2101 [pii] AID - 10.1210/jc.2009-2101 [doi] PST - ppublish SO - J Clin Endocrinol Metab. 2010 May;95(5):2384-90. doi: 10.1210/jc.2009-2101. Epub 2010 Mar 9.