Association and meta-analysis of HLA and non-obstructive azoospermia in the Han Chinese population

Abstract

The exact aetiology and pathogenesis of most non-obstructive azoospermia (NOA) are still unknown. The previous two genomewide association studies (GWASs) have identified three different loci within the HLA region for NOA in the Han Chinese population, including rs3129878, rs498422 and rs7194. To further validate the risk of three GWAS-linked loci for NOA, we conducted a case-control study of these three risk loci in an independent Han Chinese male population, with 603 NOA patients and 610 controls. Furthermore, we also performed a meta-analysis of five studies on these three NOA-risk loci. The case-control study strongly suggested a significant association between loci rs3129878, rs498422 and rs7194 and NOA (P = 6.75 × 10 (OR = 2.2586), P = 0.0060 (OR = 1.4013) and P = 0.0128 (OR = 1.2626) respectively). Our meta-analyses also supported the susceptibility of these three risk loci to NOA (P < 0.01). The risk variants within the HLA region potentially have a strong effect on males at risk of NOA, and may serve as diagnostic markers for male infertility. However, considering genetic difference between different populations, future validating studies in larger independent samples and animal experiments are suggested.

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

“…Three of these variants (rs3129878, rs498422, and rs7194) were found in the major histocompatibility complex (MHC) locus, a dense region containing approximately 150 genes that encode the human leucocyte antigen (HLA) immunoregulatory proteins (11). These three variants were further verified as NOA-risk loci by subsequent association and metaanalysis of HLA and NOA in the Han Chinese or Japanese population (12)(13)(14). However, because of the extensive linkage disequilibrium (LD) existing in the MHC region, it has been difficult to pinpoint the specific risk-associated variants.…”

Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility

“…Later on, the two GWASs performed in Chinese populations, and the follow-up study of one of them, also highlighted this genomic region as the top associated signal with NOA across the whole genome 13 – 15 . Additional evidence of the major involvement of the MHC class II in NOA was also generated by two recent studies, including an independent meta-analysis and a fine-mapping of this region using GWAS data, both from Han Chinese, in which the haplotype HLA-DRB1*1302 was confirmed as a molecular marker for NOA 41 , 42 .…”

Genetic Landscape of Nonobstructive Azoospermia and New Perspectives for the Clinic

“…Genetic associations at the genome-wide level of significance were observed in three new loci: a genomic region near IL17A (interleukin 17A, MIM*603149; encoding a proinflammatory cytokine), ABLIM1 (actin-binding LIM protein family, member 1, MIM*602330; a regulatory gene of the actin-dependent signalling), and HLA-DRA (major histocompatibility complex, class II, DR alpha, MIM*142860; encoding the alpha subunit of the HLA-DR molecule). The two latter associations were further replicated in independent Chinese populations [204,205].…”