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Open AccessArticle

A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells

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Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain
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Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina “López Neyra”, Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), 18016 Granada, Spain
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Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, 08208 Sabadell, Spain
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Departments of Immunology and Neurology, Multiple Sclerosis Unit, Hospital Ramon y Cajal, (IRYCIS), 28034 Madrid, Spain
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Lab. of Genetics of Complex Diseases, Hospital Clinico San Carlos, Instituto de Investigacion Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain
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Servicio de Neurología, Hospital Clinic and Institut d’Investigació Biomèdica Pi i Sunyer (IDIBAPS), Universitat de Barcelona, 08036 Barcelona, Spain
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Unidad de Gestión Clínica de Neurociencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, 29010 Málaga, Spain
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Girona Neuroimmunology and Multiple Sclerosis Unit, Neurology Department, Dr. Josep Trueta University Hospital, Neurodegeneration and Neuroinflammation Group, Girona Biomedical Research Institute (IdIBGi), Department of Medical Sciences, Faculty of Medicine, University of Girona, 17190 Girona, Spain
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Inflammation & Biomarkers Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain
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IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain
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Neurosciences Area, Biodonostia Health Research Institute, 20014 San Sebastián, Spain
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Servicio de Neurología, Hospital Universitario Donostia, 20014 San Sebastián, Spain
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Departamento de Neurología, Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain
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Institute of Evolutionary Biology (CSIC-UPF), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain
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Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 43200 Reus, Spain
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Centre de Regulació Genòmica (CRG), 08003 Barcelona, Spain
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Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
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Center for Multiple Sclerosis, St. Michael’s Hospital, University of Toronto, Toronto, ON M5S 1A1, Canada
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Authors to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(3), 625; https://doi.org/10.3390/jcm9030625
Received: 16 January 2020 / Revised: 19 February 2020 / Accepted: 20 February 2020 / Published: 26 February 2020
(This article belongs to the Section Clinical Neurology)
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. View Full-Text
Keywords: multiple sclerosis; genetics; targeted DNA sequencing; genotyping; single nucleotide polymorphisms; CXCR5 multiple sclerosis; genetics; targeted DNA sequencing; genotyping; single nucleotide polymorphisms; CXCR5
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Figure 1

MDPI and ACS Style

Gil-Varea, E.; Fedetz, M.; Eixarch, H.; Spataro, N.; Villar, L.M.; Urcelay, E.; Saiz, A.; Fernández, Ó.; Leyva, L.; Ramió-Torrentà, L.; Vandenbroeck, K.; Otaegui, D.; Castillo-Triviño, T.; Izquierdo, G.; Malhotra, S.; Bosch, E.; Navarro, A.; Alcina, A.; Montalban, X.; Matesanz, F.; Comabella, M. 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, 9, 625. https://doi.org/10.3390/jcm9030625

AMA Style

Gil-Varea E, Fedetz M, Eixarch H, Spataro N, Villar LM, Urcelay E, Saiz A, Fernández Ó, Leyva L, Ramió-Torrentà L, Vandenbroeck K, Otaegui D, Castillo-Triviño T, Izquierdo G, Malhotra S, Bosch E, Navarro A, Alcina A, Montalban X, Matesanz F, Comabella M. A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells. Journal of Clinical Medicine. 2020; 9(3):625. https://doi.org/10.3390/jcm9030625

Chicago/Turabian Style

Gil-Varea, Elia; Fedetz, Maria; Eixarch, Herena; Spataro, Nino; Villar, Luisa M.; 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. 2020. "A New Risk Variant for Multiple Sclerosis at 11q23.3 Locus Is Associated with Expansion of CXCR5+ Circulating Regulatory T Cells" J. Clin. Med. 9, no. 3: 625. https://doi.org/10.3390/jcm9030625

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