Association of a tagging single nucleotide polymorphism in the androgen receptor gene region with susceptibility to severe hypospadias in a Caucasian population

• Hypospadias is a congenital malformation and a milder form of 46,XY disorder of sexual development (DSD). In the present study, we investigated 13 haplotype tagging single nucleotide polymorphisms (SNPs) covering the steroid-5-alpha reductase <i>(SRD5A2)</i> and androgen receptor<i>(AR) </i>gene region, respectively, in a cohort consisting of 260 individuals with mild hypospadias and 77 with severe disease, in addition to 471 healthy male controls. The investigated genes are known to have an important role in the hormone-dependent stage of sexual development. Our study revealed one novel marker located in the <i>AR </i>gene region (rs5919436; g.67024320C>G) to be significantly associated with an increased risk of severe hypospadias (adjusted p value: 0.02; odds ratio: 2.98). In concordance with this finding, we detected an association of a haplotype tagged by the minor allele of rs5919436 (adjusted p value: 0.04). We further detected no association between the investigated disease and the haplotype tagging polymorphisms covering the <i>SRD5A2</i> gene, which is of importance considering the conflicting results reported previously. In conclusion, our data implicate that the AR rs5919436 (g.67024320C>G) polymorphism may act as a novel genetic marker for increased susceptibility to severe hypospadias in Caucasians.

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