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

Elia Gil‐Varea ,Koen Vandenbroeck,Elena Urcelay,Óscar Fernández,Laura Leyva,Guillermo Izquierdo,Nino Spataro,Manuel Comabella,Luisa María Villar,Fuencisla Matesanz,Tamara Castillo-Triviño,Herena Eixarch,Antonio Alcina,Elena Bosch,David Otaegui,Arcadi Navarro,Sunny Malhotra,Marı́a Fedetz ,Xavier Montalbán ,Lluı́s Ramió-Torrentà ,Albert Sáiz

doi:10.3390/jcm9030625

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.

Highlights

Increasing evidence indicates that both genetic and environmental factors, such as cigarette smoking, vitamin D insufficiency and Epstein-Barr virus, contribute to multiple sclerosis (MS [MIM: 126,200]) susceptibility [1]
With the objective of identifying new common genetic variants associated with MS susceptibility, we first performed targeted resequencing of 14 selected MS risk genes in a discovery cohort composed of 524 MS patients and 546 HD (n = 1070)
The minor alleles of 13 polymorphisms were found to be more frequently represented in patients with MS than in HD (OR > 1.0), which classifies them as variants associated with an increased risk for MS, while 19 were more frequently detected in HD than in MS

Summary

Introduction

Increasing evidence indicates that both genetic and environmental factors, such as cigarette smoking, vitamin D insufficiency and Epstein-Barr virus, contribute to multiple sclerosis (MS [MIM: 126,200]) susceptibility [1]. There is GWAS evidence supporting the relevance of T follicular helper cells (Tfh) in MS by identifying polymorphisms in the Tfh genes interleukin 21 (IL-21), C-X-C motif chemokine receptor 5 (CXCR5), and programmed cell death 1 (PD-1) associated with diagnosis or disease prognosis. These cells, which are involved in the formation of germinal centers and the activation, expansion and differentiation of B cells into antibody-producing cells, have been found infiltrated in the central nervous system (CNS) of MS patients, potentially contributing to the inflammatory activity of pathogenic B-cells and constituting a promising target for MS therapies [7]. We first aimed to detect novel SNP-based MS associations within 14 selected MS risk genes by means of DNA resequencing and genotyping and to identify the causal variant for the strongest association throughout specific functional studies

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