Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Gil-Varea, Elia, Fedetz, Maria, Eixarch, Herena, Spataro, Nino, Villar, Luisa María, Urcelay, Elena, Saiz, Albert, Fernández, Óscar, Leyva, Laura, Ramió-Torrentà, Lluís, Vandenbroeck, Koen, Otaegui, David, Castillo-Triviño, Tamara, Izquierdo, Guillermo, Malhotra, Sunny, Bosch, Elena, Navarro, Arcadi, Alcina, Antonio, Montalban, Xavier, Matesanz, Fuencisla, Comabella, Manuel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141122/
https://www.ncbi.nlm.nih.gov/pubmed/32110891
http://dx.doi.org/10.3390/jcm9030625
_version_ 1783519128787615744
author Gil-Varea, Elia
Fedetz, Maria
Eixarch, Herena
Spataro, Nino
Villar, Luisa María
Urcelay, Elena
Saiz, Albert
Fernández, Óscar
Leyva, Laura
Ramió-Torrentà, Lluís
Vandenbroeck, Koen
Otaegui, David
Castillo-Triviño, Tamara
Izquierdo, Guillermo
Malhotra, Sunny
Bosch, Elena
Navarro, Arcadi
Alcina, Antonio
Montalban, Xavier
Matesanz, Fuencisla
Comabella, Manuel
author_facet Gil-Varea, Elia
Fedetz, Maria
Eixarch, Herena
Spataro, Nino
Villar, Luisa María
Urcelay, Elena
Saiz, Albert
Fernández, Óscar
Leyva, Laura
Ramió-Torrentà, Lluís
Vandenbroeck, Koen
Otaegui, David
Castillo-Triviño, Tamara
Izquierdo, Guillermo
Malhotra, Sunny
Bosch, Elena
Navarro, Arcadi
Alcina, Antonio
Montalban, Xavier
Matesanz, Fuencisla
Comabella, Manuel
author_sort Gil-Varea, Elia
collection PubMed
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.
format Online
Article
Text
id pubmed-7141122
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-71411222020-04-10 A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells Gil-Varea, Elia Fedetz, Maria Eixarch, Herena Spataro, Nino Villar, Luisa María Urcelay, Elena Saiz, Albert Fernández, Óscar Leyva, Laura Ramió-Torrentà, Lluís Vandenbroeck, Koen Otaegui, David Castillo-Triviño, Tamara Izquierdo, Guillermo Malhotra, Sunny Bosch, Elena Navarro, Arcadi Alcina, Antonio Montalban, Xavier Matesanz, Fuencisla Comabella, Manuel J Clin Med Article 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. MDPI 2020-02-26 /pmc/articles/PMC7141122/ /pubmed/32110891 http://dx.doi.org/10.3390/jcm9030625 Text en © 2020 by the authors. 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/).
spellingShingle Article
Gil-Varea, Elia
Fedetz, Maria
Eixarch, Herena
Spataro, Nino
Villar, Luisa María
Urcelay, Elena
Saiz, Albert
Fernández, Óscar
Leyva, Laura
Ramió-Torrentà, Lluís
Vandenbroeck, Koen
Otaegui, David
Castillo-Triviño, Tamara
Izquierdo, Guillermo
Malhotra, Sunny
Bosch, Elena
Navarro, Arcadi
Alcina, Antonio
Montalban, Xavier
Matesanz, Fuencisla
Comabella, Manuel
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
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_short A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells
title_sort new risk variant for multiple sclerosis at 11q23.3 locus is associated with expansion of cxcr5+ circulating regulatory t cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141122/
https://www.ncbi.nlm.nih.gov/pubmed/32110891
http://dx.doi.org/10.3390/jcm9030625
work_keys_str_mv AT gilvareaelia anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT fedetzmaria anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT eixarchherena anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT spataronino anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT villarluisamaria anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT urcelayelena anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT saizalbert anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT fernandezoscar anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT leyvalaura anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT ramiotorrentalluis anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT vandenbroeckkoen anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT otaeguidavid anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT castillotrivinotamara anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT izquierdoguillermo anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT malhotrasunny anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT boschelena anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT navarroarcadi anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT alcinaantonio anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT montalbanxavier anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT matesanzfuencisla anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT comabellamanuel anewriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT gilvareaelia newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT fedetzmaria newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT eixarchherena newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT spataronino newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT villarluisamaria newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT urcelayelena newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT saizalbert newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT fernandezoscar newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT leyvalaura newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT ramiotorrentalluis newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT vandenbroeckkoen newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT otaeguidavid newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT castillotrivinotamara newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT izquierdoguillermo newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT malhotrasunny newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT boschelena newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT navarroarcadi newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT alcinaantonio newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT montalbanxavier newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT matesanzfuencisla newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells
AT comabellamanuel newriskvariantformultiplesclerosisat11q233locusisassociatedwithexpansionofcxcr5circulatingregulatorytcells