H2BFWT is one of the testis‐specific histones that plays a fundamental role in spermatogenesis, and single nucleotide polymorphisms (SNPs) in this gene may result in male infertility. This study aimed to investigate the association between −9C>T and 368A>G transitions of H2BFWT gene and male infertility through a case–control, meta‐analysis, and a bioinformatics approach. In this case–control study, 490 subjects including 240 idiopathic infertile men and 250 healthy controls were included. The −9C>T and 368A>G SNPs genotyping were performed by a PCR–RFLP method. To find eligible studies for meta‐analysis, we searched valid scientific databases. The odds ratios with 95% confidence intervals were estimated to find the strength of these associations. Furthermore, the influences of two common transitions on the molecular features of H2BFWT were assessed by in silico tools. Our case–control data revealed that −9C>T is not associated with male infertility. But, there was a significant association between 368A>G and male infertility. In the meta‐analysis, five eligible studies were included. Our data revealed significant associations between −9C>T, 368A>G, and male infertility in overall and stratified analyses. Moreover, structural analysis showed that 368A>G could affect the protein structure (SNAP prediction: non‐neutral, score: 42, expected accuracy: 71%; SIFT prediction: deleterious, score: −2.55), while −9C>T may affect the binding nucleotide in the promoter region. Based on these findings, two aforementioned polymorphisms were associated with increased risk of male infertility. However, studies with larger sample size and different ethnicities are needed to obtain more accurate conclusions.
