Polymorphic Variants of BH4 Pathway Genes and Isolated Hypospadias Risk

Background: Hypospadias (HS) is one of the most common congenital malformations. Complications of corrective surgery in HS correlate with patients’ opinions on their voiding ability and sexual life as adults. Etiology of HS involves both genetic and environmental factors. GCH1, which belongs to recently identified urothelial genes influencing voiding behavior, encodes rate-limiting enzyme catalyzing the production of tetrahydrobiopterin (BH4). A requirement for BH4, a metabolite structurally related to folic acid and riboflavin, in embryonic development was reported. Objectives: The aim of the present study was to investigate the association of selected polymorphic variants of BH4 pathway genes with hypospadias. Methods: We performed an analysis of 6 SNPs of GCH1, PAH and AGMO-DGKB loci in a group of 166 boys with isolated hypospadias and a properly matched control group. Results: There was no evidence for either allelic or genotypic association with the risk of HS for the tested nucleotide variants (rs12425434, rs7485331, rs17128050, rs8004018, rs17128077, rs2191349). The lack of association with single SNPs was confirmed at the haplotype level. The exhaustive multifactor dimensionality reduction (MDR) analysis revealed no significant interactive effect of polymorphic variants of BH4 pathway genes on HS susceptibility. Conclusions: The presented results did not support an association between SNPs of GCH1 and PAH and the risk of HS.