Association of <i>IRX6</i> rs6499755 and <i>HAAO</i> rs3816183 Polymorphisms With Hypospadias Susceptibility in Northern Chinese Han Population

<b>Background:</b> Hypospadias is one of the most common male congenital external genital malformation anomalies with unclear and multifactorial etiology. Our study aims to investigate whether <i>IRX6</i> rs6499755 and <i>HAAO</i> rs3816183 polymorphisms are susceptible to hypospadias in Chinese Northern Han. <b>Methods:</b> We enrolled 113 patients with hypospadias and 182 healthy controls in the case-control study. Genotyping of single nucleotide polymorphisms (SNPs) was performed using High Resolution Melting (HRM). 113 hypospadias cases were further divided into anterior, middle and posterior subgroups for analysis. In addition, we performed a meta-analysis to evaluate the relationship in multiple populations. <b>Results:</b> The risk allele [C] of <i>IRX6</i> rs6499755 was significantly associated with susceptibility to general hypospadias (OR = 1.547, <i>p</i>=0.01), anterior hypospadias (OR = 3.579, <i>p</i>=0.003) and posterior hypospadias (OR = 1.737, <i>p</i>=0.005). Besides, CC genotype carriers showed an increased risk of hypospadias compared with CT + TT carriers (OR = 1.832, <i>p</i>=0.026). The risk allele [T] of <i>HAAO</i> rs3816183 was associated with susceptibility to anterior/middle hypospadias (OR = 1.775, <i>p</i>=0.046). GMDR analysis revealed a significant interaction between <i>IRX6</i> rs6499755 and <i>HAAO</i> rs3816183 in the risk of hypospadias (cross-validation consistency = 10/10, testing balanced accuracy = 0.6065, <i>p</i>=0.0010). The results of meta-analysis (including 3789 cases and 9241 controls) indicated that <i>IRX6</i> rs6499755 and <i>HAAO</i> rs3816183 were significantly associated with hypospadias (both <i>p</i> < 0.00001). <b>Conclusions:</b> <i>IRX6</i> rs6499755 and <i>HAAO</i> rs3816183 polymorphisms were associated with hypospadias in Chinese Northern Han, and there is a potential interaction between <i>IRX6</i> rs6499755 and <i>HAAO</i> rs3816183 affecting the risk of hypospadias. The meta-analysis supported the hypothesis that <i>IRX6</i> rs6499755 and <i>HAAO</i> rs3816183 were the susceptibility loci for hypospadias. Further research is needed to clarify their pathogenic mechanisms.