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, E, Fedetz, M, Eixarch, H, Spataro, N, Villar, LM, Urcelay, E, Saiz, A, Fernandez, O, Leyva, L, Ramio-Torrenta, L, Vandenbroeck, K, Otaegui, D, Castillo-Trivino, T, Izquierdo, G, Malhotra, S, Bosch, E, Navarro, A, Alcina, A, Montalban, X, Matesanz, F, Comabella, M
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Institut d'Investigació i Innovació Parc Taulí (I3PT)
Repositorio:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
OAI Identifier:oai:i3pt.fundanetsuite.com:p2700
Acceso en línea:https://i3pt.portalinvestigacion.com/publicaciones/2700
Access Level:acceso abierto
Palabra clave:multiple sclerosis
genetics
targeted DNA sequencing
genotyping
single nucleotide polymorphisms
CXCR5
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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, EFedetz, MEixarch, HSpataro, NVillar, LMUrcelay, ESaiz, AFernandez, OLeyva, LRamio-Torrenta, LVandenbroeck, KOtaegui, DCastillo-Trivino, TIzquierdo, GMalhotra, SBosch, ENavarro, AAlcina, AMontalban, XMatesanz, FComabella, Mmultiple sclerosisgeneticstargeted DNA sequencinggenotypingsingle nucleotide polymorphismsCXCR5Genome-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 = 1070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5138). 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.MDPI2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://i3pt.portalinvestigacion.com/publicaciones/2700Journal of Clinical MedicineISSN: 20770383reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulíinstname:Institut d'Investigació i Innovació Parc Taulí (I3PT)Inglésinfo:eu-repo/semantics/openAccessoai:i3pt.fundanetsuite.com:p27002026-06-21T15:30:37Z
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, E
multiple sclerosis
genetics
targeted DNA sequencing
genotyping
single nucleotide polymorphisms
CXCR5
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, E
Fedetz, M
Eixarch, H
Spataro, N
Villar, LM
Urcelay, E
Saiz, A
Fernandez, O
Leyva, L
Ramio-Torrenta, L
Vandenbroeck, K
Otaegui, D
Castillo-Trivino, T
Izquierdo, G
Malhotra, S
Bosch, E
Navarro, A
Alcina, A
Montalban, X
Matesanz, F
Comabella, M
author Gil-Varea, E
author_facet Gil-Varea, E
Fedetz, M
Eixarch, H
Spataro, N
Villar, LM
Urcelay, E
Saiz, A
Fernandez, O
Leyva, L
Ramio-Torrenta, L
Vandenbroeck, K
Otaegui, D
Castillo-Trivino, T
Izquierdo, G
Malhotra, S
Bosch, E
Navarro, A
Alcina, A
Montalban, X
Matesanz, F
Comabella, M
author_role author
author2 Fedetz, M
Eixarch, H
Spataro, N
Villar, LM
Urcelay, E
Saiz, A
Fernandez, O
Leyva, L
Ramio-Torrenta, L
Vandenbroeck, K
Otaegui, D
Castillo-Trivino, T
Izquierdo, G
Malhotra, S
Bosch, E
Navarro, A
Alcina, A
Montalban, X
Matesanz, F
Comabella, M
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 multiple sclerosis
genetics
targeted DNA sequencing
genotyping
single nucleotide polymorphisms
CXCR5
topic multiple sclerosis
genetics
targeted DNA sequencing
genotyping
single nucleotide polymorphisms
CXCR5
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 = 1070) and attempted to validate a selection of signals through genotyping in an independent cohort (n = 5138). 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
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://i3pt.portalinvestigacion.com/publicaciones/2700
url https://i3pt.portalinvestigacion.com/publicaciones/2700
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Journal of Clinical Medicine
ISSN: 20770383
reponame:r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
instname:Institut d'Investigació i Innovació Parc Taulí (I3PT)
instname_str Institut d'Investigació i Innovació Parc Taulí (I3PT)
reponame_str r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
collection r-I3PT. Repositorio Institucional Producción Científica del Institut d'Investigació i Innovació Parc Taulí
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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