Association between CACNA1D polymorphisms and hypospadias in a southern Chinese population.

Background: Hypospadias is a congenital genitourinary malformation, with the etiology remaining complex and poorly understood. Despite several genes have been identified to be associated with the risk of hypospadias, current understanding of the susceptibility loci for hypospadias yet remained largely improved. The CACNA1D gene encodes calcium voltage-gated channel subunit alpha 1d and may be involved in androgen signaling. However, the genetic susceptibility of CACNA1D associated with hypospadias has yet been addressed.

Objective: To evaluate the association between CACNA1D polymorphisms and the susceptibility to hypospadias.

Methods: In this study, we accessed the association between two potential regulatory SNPs (rs3774491 and rs898415) within CACNA1D and hypospadias in a cohort of southern Chinese population which comprised of 740 cases and 948 healthy individuals. Both SNP and haplotypic associations were evaluated. Bioinformatic analysis of the regulatory abilities of the CACNA1D SNPs were carried out by utilizing public ChIP-seq and DNase-seq data. The expression of Cacna1d in mouse external genitalia and testis was evaluated by qPCR.

Results: We found that the allele C in rs3774491 and allele G in rs898415 were significantly associated with an increased risk of hypospadias, especially for proximal hypospadias. Further model-based genotypic analyses showed that these association were prominent in additive model and recessive models. Bioinformatic analyses indicated that both SNPs were colocalized with DNase and multiple histone marker across multiple tissues, suggesting the regulatory potentials for these variants. Cacna1d is detectable in both testis and external genitalia of mouse, but the expression level was more prominent in testis than that in external genitalia, suggesting tissue-specific differences in its expression.

Conclusion: Our findings provide evidence for CACNA1D as a novel predisposing gene for hypospadias, shedding new light on the genetic basis of malformation of urinary tract. Further investigations are warranted to elucidate the functional implication of CACNA1D underlying the development of hypospadias.

Level Of Evidence: N/A.