Fine mapping and functional analysis of the multiple sclerosis risk gene CD6

TY - JOUR

T1 - Fine mapping and functional analysis of the multiple sclerosis risk gene CD6

AU - Swaminathan, Bhairavi

AU - Cuapio, Angélica

AU - Alloza, Iraide

AU - Matesanz, Fuencisla

AU - Alcina, Antonio

AU - García-Barcina, Maria

AU - Fedetz, Maria

AU - Fernández, Oscar

AU - Lucas, Miguel

AU - Orpez, Teresa

AU - Pinto-Medel, M Jesus

AU - Otaegui, David

AU - Olascoaga, Javier

AU - Urcelay, Elena

AU - Ortiz, Miguel A

AU - Arroyo, Rafael

AU - Oksenberg, Jorge R

AU - Antigüedad, Alfredo

AU - Tolosa, Eva

AU - Vandenbroeck, Koen

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

KW - Adult

KW - Antigens, CD

KW - Antigens, Differentiation, T-Lymphocyte

KW - CD4-Positive T-Lymphocytes

KW - CD8-Positive T-Lymphocytes

KW - Chromosome Mapping

KW - Cluster Analysis

KW - Cytokines

KW - European Continental Ancestry Group

KW - Female

KW - Gene Order

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Haplotypes

KW - Humans

KW - Linkage Disequilibrium

KW - Lymphocyte Activation

KW - Male

KW - Multiple Sclerosis

KW - Polymorphism, Single Nucleotide

KW - Protein Interaction Domains and Motifs

KW - Spain

KW - Young Adult

U2 - 10.1371/journal.pone.0062376

DO - 10.1371/journal.pone.0062376

M3 - SCORING: Journal article

C2 - 23638056

VL - 8

SP - e62376

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 4

ER -