A single nucleotide polymorphism in a miR-1302 binding site in CGA increases the risk of idiopathic male infertility.

Objective: To explore the possible association between single nucleotide polymorphisms (SNPs) in the miRNA-binding sites of spermatogenesis-related genes and idiopathic infertility in humans.

Design: Prospective study.

Setting: Research laboratory of a university hospital.

Patient(s): A total of 494 patients with azoospermia or severe oligozoospermia and 357 fertile controls were included in our study.

Intervention(s): The 3' untranslated region sequences of 140 candidate genes for male infertility were analyzed using specialized algorithms including Pictar, miRanda, Targetscan, and RNAhybrid and 39 SNPs located at putative miRNA-binding sites were identified. The possible association of 6 putatively functional SNPs and male infertility was explored further with the use of case-control studies. The function of SNPs significantly associated with male infertility was analyzed by dual luciferase assay.

Main Outcome Measure(s): Significantly associated SNPs and their influence on gene expression.

Result(s): Two SNPs from two genes (rs6631 of CGA and rs2303846 of CPEB1) were found to be associated with idiopathic male infertility. Functionally, the substitution of A by T in rs6631 results in decreased binding affinity of miR-1302 and overexpression of CGA in vitro.

Conclusion(s): Our results reveal for the first time that SNPs residing in miRNA-binding sites of CGA could influence expression of CGA and elevate the risk of spermatogenesis impairment.