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Title: A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells
Author: Gil Varea, Elia
Fedetz, María
Eixarch, Herena
Spataro, Nino
Villar, Luisa M.
Urcelay, Elena
Saiz Hinajeros, 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
Keywords: Esclerosi múltiple
Polimorfisme genètic
Multiple sclerosis
Genetic polymorphisms
Issue Date: 26-Feb-2020
Publisher: MDPI
Abstract: 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.
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It is part of: Journal of Clinical Medicine, 2020, vol. 9, num. 3, p. 625
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ISSN: 2077-0383
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Medicina)

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