RT Journal Article
T1 A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells.
A1 Gil-Varea, Elia
A1 Fedetz, Maria
A1 Eixarch, Herena
A1 Spataro, Nino
A1 Villar, Luisa Maria
A1 Urcelay, Elena
A1 Saiz, Albert
A1 Fernandez, Oscar
A1 Leyva, Laura
A1 Ramio-Torrenta, Lluis
A1 Vandenbroeck, Koen
A1 Otaegui, David
A1 Castillo-Triviño, Tamara
A1 Izquierdo, Guillermo
A1 Malhotra, Sunny
A1 Bosch, Elena
A1 Navarro, Arcadi
A1 Alcina, Antonio
A1 Montalban, Xavier
A1 Matesanz, Fuencisla
A1 Comabella, Manuel
K1 CXCR5
K1 Genetics
K1 Genotyping
K1 Multiple sclerosis
K1 Single nucleotide polymorphisms
K1 Targeted DNA sequencing
AB 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.
PB MDPI
SN 2077-0383
YR 2020
FD 2020-02-26
LK https://hdl.handle.net/10668/26956
UL https://hdl.handle.net/10668/26956
LA en
NO Gil-Varea E, Fedetz M, Eixarch H, Spataro N, Villar LM, Urcelay E, et al. A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells. J Clin Med. 2020 Feb 26;9(3):625
NO The genotyping service was carried out at CEGEN-PRB2-ISCIII and was supported by grant PT13/0001, ISCIII-SGEFI/FEDER. This work was also supported by the following grants: BFU2016-77961-P (AEI/FEDER); 2017-SGR-00702 (Direcció General de Recerca, Generalitat de Catalunya); Unidad de Excelencia María de Maeztu funded by the MINECO (MDM-2014-0370); Proyectos de Investigación en Salud (FIS PI12/02229, PI15/00587, PI16/01259); Red Española de Esclerosis Múltiple (RD16/0015/0004 to M.C., RD16/0015/0002; RD16/0015/0005 to K.V.; RD16/0015/0016) integrated in the Plan Estatal I+D+I and cofunded by Instituto de Salud Carlos III and the Fondo Europeo de Desarrollo Regional (FEDER; “Otra forma de hacer Europa”); SAF2016-80595-C2-1-P (Ministerio de Economía, Industria y Competitividad).
DS RISalud
RD Apr 17, 2025