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, Fedetz, María, Eixarch, Herena, Spataro, Nino, Villar, Luisa M., Urcelay, Elena, Saiz Hinarejos, Albert, Fernández, Óscar, Leyva, Laura, Ramió Torrentà, Lluís, Vandenbroeck, Koen, Otaegui, David, Castillo Triviño, Tamara, Izquierdo, Guillermo, Malhotra, Sunny, Bosch, Elena, Navarro i Cuartiellas, Arcadi, 1969-, Alcina, Antonio, Montalbán Gairín, Xavier, Matesanz, Fuencisla, Comabella, 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:2445/176047
Acceso en línea:https://hdl.handle.net/2445/176047
Access Level:acceso abierto
Palabra clave:Esclerosi múltiple
Genètica
Polimorfisme genètic
Multiple sclerosis
Genetics
Genetic polymorphisms
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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, EliaFedetz, MaríaEixarch, HerenaSpataro, NinoVillar, Luisa M.Urcelay, ElenaSaiz Hinarejos, AlbertFernández, ÓscarLeyva, LauraRamió Torrentà, LluísVandenbroeck, KoenOtaegui, DavidCastillo Triviño, TamaraIzquierdo, GuillermoMalhotra, SunnyBosch, ElenaNavarro i Cuartiellas, Arcadi, 1969-Alcina, AntonioMontalbán Gairín, XavierMatesanz, FuencislaComabella, ManuelEsclerosi múltipleGenèticaPolimorfisme genèticMultiple sclerosisGeneticsGenetic polymorphismsGenome-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.MDPI2021202120202021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion22 p.application/pdfhttps://hdl.handle.net/2445/176047Articles publicats en revistes (Medicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.3390/jcm9030625Journal of Clinical Medicine, 2020, vol. 9, num. 3, p. 625https://doi.org/10.3390/jcm9030625cc-by (c) Gil Varea, Elia et al., 2020http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/1760472026-05-29T05:05:01Z
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
Polimorfisme genètic
Multiple sclerosis
Genetics
Genetic polymorphisms
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
Fedetz, María
Eixarch, Herena
Spataro, Nino
Villar, Luisa M.
Urcelay, Elena
Saiz Hinarejos, Albert
Fernández, Óscar
Leyva, Laura
Ramió Torrentà, Lluís
Vandenbroeck, Koen
Otaegui, David
Castillo Triviño, Tamara
Izquierdo, Guillermo
Malhotra, Sunny
Bosch, Elena
Navarro i Cuartiellas, Arcadi, 1969-
Alcina, Antonio
Montalbán Gairín, Xavier
Matesanz, Fuencisla
Comabella, Manuel
author Gil Varea, Elia
author_facet Gil Varea, Elia
Fedetz, María
Eixarch, Herena
Spataro, Nino
Villar, Luisa M.
Urcelay, Elena
Saiz Hinarejos, Albert
Fernández, Óscar
Leyva, Laura
Ramió Torrentà, Lluís
Vandenbroeck, Koen
Otaegui, David
Castillo Triviño, Tamara
Izquierdo, Guillermo
Malhotra, Sunny
Bosch, Elena
Navarro i Cuartiellas, Arcadi, 1969-
Alcina, Antonio
Montalbán Gairín, Xavier
Matesanz, Fuencisla
Comabella, Manuel
author_role author
author2 Fedetz, María
Eixarch, Herena
Spataro, Nino
Villar, Luisa M.
Urcelay, Elena
Saiz Hinarejos, Albert
Fernández, Óscar
Leyva, Laura
Ramió Torrentà, Lluís
Vandenbroeck, Koen
Otaegui, David
Castillo Triviño, Tamara
Izquierdo, Guillermo
Malhotra, Sunny
Bosch, Elena
Navarro i Cuartiellas, Arcadi, 1969-
Alcina, Antonio
Montalbán Gairín, Xavier
Matesanz, Fuencisla
Comabella, Manuel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Esclerosi múltiple
Genètica
Polimorfisme genètic
Multiple sclerosis
Genetics
Genetic polymorphisms
topic Esclerosi múltiple
Genètica
Polimorfisme genètic
Multiple sclerosis
Genetics
Genetic polymorphisms
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
2021
2021
2021
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 https://hdl.handle.net/2445/176047
url https://hdl.handle.net/2445/176047
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/jcm9030625
Journal of Clinical Medicine, 2020, vol. 9, num. 3, p. 625
https://doi.org/10.3390/jcm9030625
dc.rights.none.fl_str_mv cc-by (c) Gil Varea, Elia et al., 2020
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Gil Varea, Elia et al., 2020
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 22 p.
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Medicina)
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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score 15.811543

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