A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells

Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 loci associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional...

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Autores: Gil-Varea, Elia, Bosch Fusté, Elena, Navarro i Cuartiellas, Arcadi, 1969-, Comabella López, Manuel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/44435
Acceso en línea:http://hdl.handle.net/10230/44435
http://dx.doi.org/10.3390/jcm9030625
Access Level:acceso abierto
Palabra clave:Esclerosi múltiple
Genètica
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spelling A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cellsGil-Varea, EliaBosch Fusté, ElenaNavarro i Cuartiellas, Arcadi, 1969-Comabella López, ManuelEsclerosi múltipleGenèticaGenome-wide association studies and meta-analysis have contributed to the identification of more than 200 loci associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals (n = 1,070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5,138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (CXCR5), Ts translation elongation factor, mitochondrial (TSFM) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Rs10892307 resulted in a new signal at the CXCR5 region that explains one of the associations with MS within the locus. This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the CXCR5 MS risk locus and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association.Funding: The genotyping service was carried out at CEGEN-PRB2-ISCIII and was supported by grant PT13/0001, ISCIII-SGEFI/FEDER. This work was also supported by the following grants: BFU2016-77961-P (AEI/FEDER); 2017-SGR-00702 (Direcció General de Recerca, Generalitat de Catalunya); Unidad de Excelencia María de Maeztu funded by the MINECO (MDM-2014-0370); Proyectos de Investigación en Salud (FIS PI12/02229, PI15/00587, PI16/01259); Red Española de Esclerosis Múltiple (RD16/0015/0004 to M.C., RD16/0015/0002; RD16/0015/0005 to K.V.; RD16/0015/0016) integrated in the Plan Estatal I+D+I and cofunded by Instituto de Salud Carlos III and the Fondo Europeo de Desarrollo Regional (FEDER; “Otra forma de hacer Europa”); SAF2016-80595-C2-1-P (Ministerio de Economía, Industria y Competitividad)MDPI202020202020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/44435http://dx.doi.org/10.3390/jcm9030625reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésJournal of Clinical Medicine. 2020 Feb 26; 9(3). pii: E625info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-Pinfo:eu-repo/grantAgreement/ES/1PE/SAF2016-80595-C2-1-P© 2020 by Elia Gil-Varea et al. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/444352026-05-29T05:05:01Z
dc.title.none.fl_str_mv A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells
title A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells
spellingShingle A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells
Gil-Varea, Elia
Esclerosi múltiple
Genètica
title_short A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells
title_full A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells
title_fullStr A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells
title_full_unstemmed A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells
title_sort A new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of CXCR5+ circulating regulatory T cells
dc.creator.none.fl_str_mv Gil-Varea, Elia
Bosch Fusté, Elena
Navarro i Cuartiellas, Arcadi, 1969-
Comabella López, Manuel
author Gil-Varea, Elia
author_facet Gil-Varea, Elia
Bosch Fusté, Elena
Navarro i Cuartiellas, Arcadi, 1969-
Comabella López, Manuel
author_role author
author2 Bosch Fusté, Elena
Navarro i Cuartiellas, Arcadi, 1969-
Comabella López, Manuel
author2_role author
author
author
dc.subject.none.fl_str_mv Esclerosi múltiple
Genètica
topic Esclerosi múltiple
Genètica
description Genome-wide association studies and meta-analysis have contributed to the identification of more than 200 loci associated with multiple sclerosis (MS). However, a proportion of MS heritability remains unknown. We aimed to uncover new genetic variants associated with MS and determine their functional effects. For this, we resequenced the exons and regulatory sequences of 14 MS risk genes in a cohort of MS patients and healthy individuals (n = 1,070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5,138). We identified three new MS-associated variants at C-X-C motif chemokine receptor 5 (CXCR5), Ts translation elongation factor, mitochondrial (TSFM) and cytochrome P450 family 24 subfamily A member 1 (CYP24A1). Rs10892307 resulted in a new signal at the CXCR5 region that explains one of the associations with MS within the locus. This polymorphism and three others in high linkage disequilibrium mapped within regulatory regions. Of them, rs11602393 showed allele-dependent enhancer activity in the forward orientation as determined by luciferase reporter assays. Immunophenotyping using peripheral blood mononuclear cells from MS patients associated the minor allele of rs10892307 with increased percentage of regulatory T cells expressing CXCR5. This work reports a new signal for the CXCR5 MS risk locus and points to rs11602393 as the causal variant. The expansion of CXCR5+ circulating regulatory T cells induced by this variant could cause its MS association.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/44435
http://dx.doi.org/10.3390/jcm9030625
url http://hdl.handle.net/10230/44435
http://dx.doi.org/10.3390/jcm9030625
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Journal of Clinical Medicine. 2020 Feb 26; 9(3). pii: E625
info:eu-repo/grantAgreement/ES/1PE/BFU2016-77961-P
info:eu-repo/grantAgreement/ES/1PE/SAF2016-80595-C2-1-P
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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