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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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 |
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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 |
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