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

2022-11-10Journal article Open access
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dc.contributor.authorCerván-Martín, Miriam
dc.contributor.authorTüttelmann, Frank
dc.contributor.authorLopes, Alexandra M.
dc.contributor.authorBossini-Castillo, Lara
dc.contributor.authorRivera-Egea, Rocío
dc.contributor.authorGarrido, Nicolás
dc.contributor.authorLujan, Saturnino
dc.contributor.authorRomeu, Gema
dc.contributor.authorSantos-Ribeiro, Samuel
dc.contributor.authorCastilla, José 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.authorGuzmán-Jiménez, Andrea
dc.contributor.authorBurgos, Miguel
dc.contributor.authorJiménez, Rafael
dc.contributor.authorPacheco, Alberto
dc.contributor.authorGonzález, Cristina
dc.contributor.authorGómez, Susana
dc.contributor.authorAmorós, 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, Sónia
dc.contributor.authorSánchez-Curbelo, Josvany
dc.contributor.authorLópez-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.date.accessioned2023-03-20T14:05:43Z
dc.date.available2023-03-20T14:05:43Z
dc.date.issued2022-11-10
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.pt_PT
dc.description.sponsorshipThis 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”).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCommun Biol. 2022 Nov 10;5(1):1220. doi: 10.1038/s42003-022-04192-0.pt_PT
dc.identifier.doi10.1038/s42003-022-04192-0pt_PT
dc.identifier.issn2399-3642
dc.identifier.urihttp://hdl.handle.net/10400.18/8572
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relation2013 - Strategic Project
dc.relationUnderstanding the basis of semen hyperviscosity and asthenozoospermia phenotypes - a systems biology approach
dc.relationCentre for Toxicogenomics and Human Health
dc.relationCentre for Toxicogenomics and Human Health
dc.relationCentre for Toxicogenomics and Human Health
dc.relation.publisherversionhttps://www.nature.com/articles/s42003-022-04192-0pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAllelespt_PT
dc.subjectGenome-Wide Association Studypt_PT
dc.subjectSpermatogenesispt_PT
dc.subjectInfertility, Malept_PT
dc.subjectGeneticspt_PT
dc.subjectMetabolism Malept_PT
dc.subjectIntracellular Signaling Peptides and Proteinspt_PT
dc.subjectProtein Serine-Threonine Kinasespt_PT
dc.subjectSertoli Cellspt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleImmune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertilitypt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitle2013 - Strategic Project
oaire.awardTitleUnderstanding the basis of semen hyperviscosity and asthenozoospermia phenotypes - a systems biology approach
oaire.awardTitleCentre for Toxicogenomics and Human Health
oaire.awardTitleCentre for Toxicogenomics and Human Health
oaire.awardTitleCentre for Toxicogenomics and Human Health
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6820 - DCRRNI ID/PEst-C%2FSAU%2FLA0003%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F120777%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/Investigador FCT/IF%2F01262%2F2014%2FCP1245%2FCT0001/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F00009%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00009%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F00009%2F2020/PT
oaire.citation.issue1pt_PT
oaire.citation.startPage1220pt_PT
oaire.citation.titleCommunications Biologypt_PT
oaire.citation.volume5pt_PT
oaire.fundingStream6820 - DCRRNI ID
oaire.fundingStreamInvestigador FCT
oaire.fundingStream6817 - DCRRNI ID
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
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rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
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