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

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dc.contributor.authorCervan-Martin, Miriam
dc.contributor.authorTüttelmann, Frank
dc.contributor.authorLopes, Alexandra M
dc.contributor.authorBossini-Castillo, Lara
dc.contributor.authorRivera-Egea, Rocio
dc.contributor.authorGarrido, Nicolas
dc.contributor.authorLujan, Saturnino
dc.contributor.authorRomeu, Gema
dc.contributor.authorSantos-Ribeiro, Samuel
dc.contributor.authorCastilla, Jose A
dc.contributor.authorCarmen Gonzalvo, M
dc.contributor.authorClavero, Ana
dc.contributor.authorMaldonado, Vicente
dc.contributor.authorVicente, F Javier
dc.contributor.authorGonzález-Muñoz, Sara
dc.contributor.authorGuzman-Jimenez, Andrea
dc.contributor.authorBurgos, Miguel
dc.contributor.authorJimenez, Rafael
dc.contributor.authorPacheco, Alberto
dc.contributor.authorGonzalez, Cristina
dc.contributor.authorGomez, Susana
dc.contributor.authorAmoros, David
dc.contributor.authorAguilar, Jesus
dc.contributor.authorQuintana, Fernando
dc.contributor.authorCalhaz-Jorge, Carlos
dc.contributor.authorAguiar, Ana
dc.contributor.authorNunes, Joaquim
dc.contributor.authorSousa, Sandra
dc.contributor.authorPereira, Isabel
dc.contributor.authorPinto, Maria Graça
dc.contributor.authorCorreia, Sonia
dc.contributor.authorSanchez-Curbelo, Josvany
dc.contributor.authorLopez-Rodrigo, Olga
dc.contributor.authorMartín, Javier
dc.contributor.authorPereira-Caetano, Iris
dc.contributor.authorMarques, Patricia I
dc.contributor.authorCarvalho, Filipa
dc.contributor.authorBarros, Alberto
dc.contributor.authorGromoll, Jörg
dc.contributor.authorBassas, Lluís
dc.contributor.authorSeixas, Susana
dc.contributor.authorGonçalves, João
dc.contributor.authorLarriba, Sara
dc.contributor.authorKliesch, Sabine
dc.contributor.authorPalomino-Morales, Rogelio J
dc.contributor.authorCarmona, F David
dc.contributor.funderSpanish Ministry of Science through the Spanish National Plan for Scientific and Technical Research and Innovation (PAIDI 2020)
dc.contributor.funderAndalusian Plan for Research and Innovation
dc.contributor.funderR+D+i Projects of the FEDER Operational Programme 2020
dc.date.accessioned2023-05-03T13:26:52Z
dc.date.available2023-05-03T13:26:52Z
dc.date.issued2022-10-28
dc.description.abstractWe 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.
dc.description.sponsorshipWe thank the National DNA Bank Carlos III (University of Salamanca, Spain) for supplying part of the control DNA samples from Spain and all the participants for their essential collaboration. This work was supported by the Spanish Ministry of Science through the Spanish National Plan for Scientific and Technical Research and Innovation (refs. SAF2016-78722-R and PID2020-120157RB-I00), the Andalusian Plan for Research and Innovation (PAIDI 2020) (ref. PY20_00212), and the R+D+i Projects of the FEDER Operational Programme 2020 (ref. B-CTS-584-UGR20). F.D.C. was supported by the “Ramón y Cajal” programme (ref. RYC-2014-16458), and L.B.C. was supported by the Spanish Ministry of Economy and Competitiveness through the “Juan de la Cierva Incorporación” programme (ref. IJC2018-038026-I, funded by MCIN/AEI /10.13039/501100011033), all of them including FEDER funds. A.G.J. was funded by MCIN/AEI /10.13039/501100011033 and FSE “El FSE invierte en tu futuro” (ref. FPU20/02926). IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds (projects PEstC/SAU/LA0003/2013 and POCI-01-0145-FEDER-007274). A.M.L. is funded by the Portuguese Government through FCT (IF/01262/2014). P.I.M. is supported by the FCT post-doctoral fellowship (SFRH/BPD/120777/2016), financed from the Portuguese State Budget of the Ministry for Science, Technology and High Education and from the European Social Fund, available through the Programa Operacional do Capital Humano. ToxOmics—Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, Nova Medical School, Lisbon, is also partially supported by FCT (Projects: UID/BIM/00009/2013 and UIDB/UIDP/00009/2020). SLarriba received support from “Instituto de Salud Carlos III” (grant DTS18/00101], co-funded by FEDER funds/European Regional Development Fund (ERDF)—a way to build Europe), and from “Generalitat de Catalunya” (grant 2017SGR191). SLarriba is sponsored by the “Researchers Consolidation Programme” from the SNS-Departament de Salut Generalitat de Catalunya (Exp. CES09/020). The German cohort was recruited within the Male Reproductive Genomics (MERGE) study and supported by the German Research Foundation Clinical Research Unit ‘Male Germ Cells’ (DFG CRU326, grants to F.T. and J.G.). This article is related to the Ph.D. Doctoral Thesis of Miriam Cerván-Martín (grant ref. BES-2017-081222 funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro”).
dc.description.versionSi
dc.identifier.citationCerván-Martín M, Tüttelmann F, Lopes AM, Bossini-Castillo L, Rivera-Egea R, Garrido N, et al. Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility. Commun Biol. 2022 Nov 10;5(1):1220.
dc.identifier.doi10.1038/s42003-022-04192-0
dc.identifier.essn2399-3642
dc.identifier.pmcPMC9649734
dc.identifier.pmid36357561
dc.identifier.pubmedURLhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9649734/pdf
dc.identifier.unpaywallURLhttps://www.nature.com/articles/s42003-022-04192-0.pdf
dc.identifier.urihttp://hdl.handle.net/10668/19635
dc.issue.number1
dc.journal.titleCommunications biology
dc.journal.titleabbreviationCommun Biol
dc.language.isoen
dc.organizationHospital Universitario Virgen de las Nieves
dc.organizationInstituto de Investigación Biosanitaria de Granada (ibs.GRANADA)
dc.organizationHospital Universitario de Jaén
dc.page.number13
dc.publisherNature Publishing Group
dc.pubmedtypeJournal Article
dc.pubmedtypeResearch Support, Non-U.S. Gov't
dc.relation.projectIDSAF2016-78722-R
dc.relation.projectIDPID2020-120157RB-I00
dc.relation.projectIDPY20_00212
dc.relation.projectIDB-CTS-584-UGR20
dc.relation.publisherversionhttps://doi.org/10.1038/s42003-022-04192-0
dc.rightsAttribution 4.0 International
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectHumans
dc.subjectMale
dc.subjectGenome-Wide Association Study
dc.subjectInfertility, Male
dc.subject.decsAlelos
dc.subject.decsCélulas de Sertoli
dc.subject.decsEspermatogénesis
dc.subject.decsProteínas serina-treonina quinasas
dc.subject.decsPéptidos y proteínas de señalización intracelular
dc.subject.meshSpermatogenesis
dc.subject.meshSertoli Cells
dc.subject.meshAlleles
dc.subject.meshProtein Serine-Threonine Kinases
dc.subject.meshIntracellular Signaling Peptides and Proteins
dc.titleImmune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility.
dc.typeresearch article
dc.type.hasVersionVoR
dc.volume.number5
dspace.entity.typePublication

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