Genetics of hypospadias.
Purpose Hypospadias shows familial clustering to some extent. The most consistent explanation for this is a multifactorial pattern of inheritance, implicating a combination of genes and environment. As anti-androgenic endocrine disruptors increase the risk of hypospadias, male hormones such as dihydrotesosterone (DHT) could be involved in the etiology of this malformation. DHT stimulates development of the genital tubercle in the external genitalia. The gene encoding 17-beta-hydroxysteroid-dehydrogenase (HSD17B3), which catalyzes the conversion of androstenedione to testosterone, and the gene encoding steroid-5-alpha-reductase type II (SRD5A2), which catalyzes the conversion of testosterone to DHT might be associated with hypospadias. The aim of this study was to investigate the association of one polymorphism in each of these genes with hypospadias. Material and methods A family-based design was used for this study. Blood or saliva was collected from 195 patients and both of their parents. The polymorphism in HSD17B3 (rs1810711) was genotyped using pyrosequencing and the polymorphism in SRD5A2 (rs523349, V89L) was analysed by Restriction Fragment Length Polymorphism Analysis. The Hardy-Weinberg equilibrium was tested to identify possible systematic errors in genotyping. The Transmission Disequilibrium Test was used to test the association of the variant allele with hypospadias. Only heterozygous parents are taken into account in this latter analysis. Results No deviation from Hardy-Weinberg equilibrium was observed for the polymorphisms in HSD17B3 and SRD5A2. For the polymorphism in HSD17B3, heterozygous parents transmitted the common allele 85 times and the variant allele 94 times. This difference was not statistically significant (p = 0.501). For the polymorphism in SRD5A2, the common allele was transmitted 91 times and the polymorphic allele 81 times (p = 0.446). Conclusions The two polymorphisms analysed in this study showed no association with hypospadias. Additional polymorphisms in these or other genes need to be genotyped before conclusions about involvement of the genes in hypospadias etiology can be drawn.