Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility
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AuthorCerván Martín, Miriam; Bossini Castillo, Lara María; González Muñoz, Sara; Guzmán Jiménez, Andrea; Burgos Poyatos, Miguel; Jiménez Medina, Rafael; Palomino Morales, Rogelio Jesús; Carmona López, Francisco David
Cerván-Martín, M., Tüttelmann, F., Lopes, A.M. et al. Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility. Commun Biol 5, 1220 (2022). [https://doi.org/10.1038/s42003-022-04192-0]
SponsorshipAndalusian Plan for Research and Innovation; Juan de la Cierva Incorporación IJC2018-038026-I; Ministry for Science, Technology and High Education; BES-2017-081222, MCIN/AEI/10.13039/501100011033; National Funds IF/01262/2014, PEstC/SAU/LA0003/2013, POCI-01-0145-FEDER-007274, SFRH/BPD/120777/2016; PAIDI 2020 PY20_00212; R+D+i Projects B-CTS-584-UGR20, RYC-2014-16458; Faculty of Science and Engineering, University of Manchester FPU20/02926; Deutsche Forschungsgemeinschaft DFG CRU326; Fundação para a Ciência e a Tecnologia; Generalitat de Catalunya 2017SGR191; Ministerio de Economía y Competitividad; Instituto de Salud Carlos III DTS18/00101; Ministerio de Ciencia e Innovación; European Social Fund UIDB/UIDP/00009/2020; European Regional Development Fund; Fundació Catalana de Trasplantament; Departament de Salut, Generalitat de Catalunya CES09/020; Programa Operacional Temático Factores de Competitividade; Spanish National Plan for Scientific and Technical Research and Innovation PID2020-120157RB-I00, SAF2016-78722-R
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.