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

Altres ajuts: Andalusian Plan for Research and Innovation (PAIDI 2020) (ref. PY20_00212); R+D+i Projects of the FEDER Operational Programme 2020; Portuguese Foundation for Science and Technology (FCT) (projects PEstC/SAU/LA0003/2013, POCI-01-0145-FEDER-007274); Portuguese Government (FCT projects IF/01262/2014, UID/BIM/00009/2013, UIDB/UIDP/00009/2020); Portuguese State Budget of the Ministry for Science, Technology and High Education (SFRH/BPD/120777/2016); SNS-Departament de Salut, Generalitat de Catalunya; German Research Foundation Clinical Research Unit 'Male Germ Cells' (DFG CRU326). We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.32E-08, OR = 1.80) and an upstream locus of VRK1 (rs115054029, P = 4.24E-08, OR = 3.14), which encodes a protein kinase involved in the regulation of spermatogenesis. The SCO-associated rs1136759 allele (G) determines a serine in the position 13 of the HLA-DRβ1 molecule located in the antigen-binding pocket. Overall, our data support the notion of unexplained SPGF as a complex trait influenced by common variation in the genome, with the SCO phenotype likely representing an immune-mediated condition.