Genetics of hypospadias: are single-nucleotide polymorphisms in SRD5A2, ESR1, ESR2, and ATF3 really associated with the malformation?
BACKGROUND
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).


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.
van der Zanden
Loes F M
LF
Department of Epidemiology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
van Rooij
Iris A L M
IA
Feitz
Wout F J
WF
Vermeulen
Sita H H M
SH
Kiemeney
Lambertus A L M
LA
Knoers
Nine V A M
NV
Roeleveld
Nel
N
Franke
Barbara
B
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics*; D051700:Activating Transcription Factor 3 / Q000235:genetics*; D002648:Child; D003456:Cryptorchidism / Q000235:genetics / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007021:Hypospadias / Q000145:classification / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009426:Netherlands; D010413:Penis / Q000002:abnormalities; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D012611:Scrotum / Q000002:abnormalities; D044465:White People / Q000235:genetics
C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008565:Membrane Proteins; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548468:SRD5A2 protein, human