title: Fine mapping and functional analysis of the multiple sclerosis risk gene CD6.
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 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.
authors: Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), Leioa, Spain.
authors: Bhairavi
authors: B
authors: Swaminathan
authors: Angélica
authors: A
authors: Cuapio
authors: Iraide
authors: I
authors: Alloza
authors: Fuencisla
authors: F
authors: Matesanz
authors: Antonio
authors: A
authors: Alcina
authors: Maria
authors: M
authors: García-Barcina
authors: Maria
authors: M
authors: Fedetz
authors: Oscar
authors: O
authors: Fernández
authors: Miguel
authors: M
authors: Lucas
authors: Teresa
authors: T
authors: Orpez
authors: M Jesus
authors: MJ
authors: Pinto-Medel
authors: David
authors: D
authors: Otaegui
authors: Javier
authors: J
authors: Olascoaga
authors: Elena
authors: E
authors: Urcelay
authors: Miguel A
authors: MA
authors: Ortiz
authors: Rafael
authors: R
authors: Arroyo
authors: Jorge R
authors: JR
authors: Oksenberg
authors: Alfredo
authors: A
authors: Antigüedad
authors: Eva
authors: E
authors: Tolosa
authors: Koen
authors: K
authors: Vandenbroeck
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002874:Chromosome Mapping; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D005260:Female; D023061:Gene Order; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D054730:Protein Interaction Domains and Motifs; D013030:Spain; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C062279:CD6 antigen; D016207:Cytokines
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