Abstract
CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2nd SRCR domain with susceptibility to MS (P max(T) permutation = 1×10−4). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. – CD4+ naïve cells, P = 0.0001; CD8+ naïve cells, P<0.0001; CD4+ and CD8+ central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4+ and CD8+ T cells.
Highlights
Multiple sclerosis (MS) is a disorder of the central nervous system that is characterized by chronic inflammation, demyelination, axonal loss and neurodegeneration [1]
Thirteen single nucleotide polymorphism (SNP) are situated in the extracellular domain region, which is divided into two linkage disequilibrium (LD) blocks by a recombination spot with a maximum recombination rate of 21.9 cM/Mb (Figure 1), while rs650258 is located between CD6 and CD5 on a recombination peak with maximum rates of 11.12 cM/Mb and 31.4 cM/Mb respectively
We aimed to identify the most important MSassociated CD6 SNP variants through a fine-mapping exercise
Summary
Multiple sclerosis (MS) is a disorder of the central nervous system that is characterized by chronic inflammation, demyelination, axonal loss and neurodegeneration [1]. Genome-wide association (GWAS) screens and meta-analyses have enabled identification of about 50 non-HLA MS risk genes [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. Apart from the HLA region, the implicated genes exert modest effects at the population level with odds ratios (OR) ranging from 1.1–1.3 [17]. The ligand for CD6 is the Activated Leukocyte Cell Adhesion Molecule (ALCAM), found in the thymic epithelium and in the epithelial layer of the blood-brain barrier. ALCAM binds to the third SRCR domain of CD6 and this interaction was recently shown to enable transmigration of CD4+ T lymphocytes across the blood-brain barrier [26]
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