Fine mapping the MHC region identified rs4997052 as a new variant associated with nonobstructive azoospermia in Han Chinese males

Objective To investigate the association between genetic variants in the major histocompatibility complex (MHC) region and nonobstructive azoospermia (NOA) susceptibility. Design MHC region fine-mapping analysis based on previous NOA genome-wide association study (GWAS) data. Setting Medical university. Patient(s) Nine hundred and eighty-one men with NOA and 1,657 normal fertile male controls. Intervention(s) None. Main Outcome Measure(s) The MHC region imputation assessed with SNP2HLA software, taking the specific Han-MHC database as a reference panel; statistical significance of the MHC variants calculated using logistic regression models; functional annotation based on online public databases; and phenotypic variances explained by specific groups of genetic variants estimated using the fixed effects model from individual associations. Result(s) Two independent risk loci, rs7194 (odds ratio [OR] 1.37) at MHC class II molecules and rs4997052 (OR 1.30) at MHC class I molecules, were identified. Functional annotation showed rs7194 may tag the effect of multiple amino acid residues and the expression of HLA-DQB1 and HLA-DRB1 ; while rs4997052 showed the effect of amino acid changes of HLA-B at position 116 as well as the expression of HLA-B and CCHCR1 , which coexpressed with genes enriched in pathways of spermatogenesis and male gamete generation. The novel variant rs4997052 identified in our study can explain another approximately 0.66% of the phenotypic variances of NOA. Conclusion(s) We fine-mapped the MHC region and identified two loci that independently drove NOA susceptibility. These results provide a deeper understanding of the association mechanisms of MHC and NOA risk.