Fine Mapping and Functional Analysis of the Multiple Sclerosis Risk Gene CD6

• Published in: PloS one Vol. 8; no. 4; p. e62376
• Main Authors: Swaminathan, Bhairavi, Cuapio, Angélica, Alloza, Iraide, Matesanz, Fuencisla, Alcina, Antonio, García-Barcina, Maria, Fedetz, Maria, Fernández, Óscar, Lucas, Miguel, Órpez, Teresa, Pinto-Medel, Mª Jesus, Otaegui, David, Olascoaga, Javier, Urcelay, Elena, Ortiz, Miguel A., Arroyo, Rafael, Oksenberg, Jorge R., Antigüedad, Alfredo, Tolosa, Eva, Vandenbroeck, Koen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.04.2013; Public Library of Science (PLoS)
• Subjects: Adult; Analysis; Antigens, CD - chemistry; Antigens, CD - genetics; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - chemistry; Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Differentiation, T-Lymphocyte - metabolism; Bioinformatics; Biology; Blood-brain barrier; Brain research; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD6 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cell surface; Chromosome Mapping; Cluster Analysis; Collection; Computer memory; Cytokines; Cytokines - secretion; Effector cells; European Continental Ancestry Group - genetics; Female; Functional analysis; Gene mapping; Gene Order; Genetic aspects; Genetic Loci; Genetic Predisposition to Disease; Genomes; Haplotypes; Humans; Immunological memory; Immunology; Inflammation; Kinases; Laboratories; Ligands; Linkage Disequilibrium; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Male; Medicine; Memory cells; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - metabolism; Natural killer cells; Nervous system; Neurology; Neurosciences; Permutations; Polymorphism; Polymorphism, Single Nucleotide; Protein Interaction Domains and Motifs; Risk; Risk factors; Scavenger receptors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Spain; Young Adult; Spain; San Francisco California; California; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0062376

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 2(nd) 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.