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| Home > Articles > Published articles > A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells |
| Home > Articles > Published articles > A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells |
(Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron) (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT)) (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid)) (Institut d'Investigacions Biomèdiques August Pi i Sunyer) (Instituto de Investigación Biomédica de Málaga) (Universitat de Girona) (IKERBASQUE (Bilbao)) (Biodonostia Osasun Ikerketako Institutura (País Basc)) (Hospital Universitario Virgen Macarena (Sevilla, Andalusia)) (Hospital Universitari Vall d'Hebron) (Centro de Investigación Biomédica en Red de Salud Mental) (Institució Catalana de Recerca i Estudis Avançats) (University of Toronto) (Instituto de Parasitología y Biomedicina "López-Neyra") (Hospital Universitari Vall d'Hebron)| Date: | 2020 |
| 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 = 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. |
| Grants: | Ministerio de Economía y Competitividad PT13/0001 Ministerio de Economía y Competitividad MDM-2014-0370 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017-SGR-00702 Ministerio de Economía y Competitividad PI15/00587 Ministerio de Economía y Competitividad PI12/02229 Ministerio de Economía y Competitividad PI16/01259 Ministerio de Economía y Competitividad RD16/0015/0004 Ministerio de Economía y Competitividad RD16/0015/0002 Ministerio de Economía y Competitividad RD16/0015/0005 Ministerio de Economía y Competitividad RD16/0015/0016 Ministerio de Economía y Competitividad SAF2016-80595-C2-1-P |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Multiple sclerosis ; Genetics ; Targeted DNA sequencing ; Genotyping ; Single nucleotide polymorphisms ; CXCR5 |
| Published in: | Journal of clinical medicine, Vol. 9 (february 2020) , ISSN 2077-0383 |
