1. Fine mapping and functional analysis of the multiple sclerosis risk gene CD6
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Rafael Arroyo, Bhairavi Swaminathan, Elena Urcelay, David Otaegui, Mª Jesus Pinto-Medel, Antonio Alcina, Koen Vandenbroeck, Alfredo Antigüedad, Fuencisla Matesanz, Miguel Lucas, María García-Barcina, María Fedetz, Oscar Fernandez, Eva Tolosa, Angelica Cuapio, Teresa Órpez, Javier Olascoaga, Miguel A. Ortiz, Iraide Alloza, Jorge R. Oksenberg, [Swaminathan,B, Alloza,I, Vandenbroeck,K] Neurogenomiks Laboratory, University of the Basque Country (UPV/EHU), Leioa, Spain. [Cuapio,A, Tolosa,E] Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [Matesanz,F, Alcina,A, Fedetz,M] Instituto de Parasitología y Biomedicina 'López Neyra' Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain. [García-Barcina,M] Servicio de Genética, Hospital de Basurto, Bilbao, Spain. [Fernández,O] Department of Neurology, Institute of Clinical Neurosciences, Hospital Regional Universitario Carlos Haya, Málaga, Spain. [ Lucas,M] Unidad de Esclerosis Múltiple, Hospital Virgen Macarena, Sevilla, Spain. [Orpez,T, Pinto-Medel,MJ] Research Laboratory, Institute of Clinical Neurosciences, Hospital Regional Universitario Carlos Haya, Málaga, Spain. [Otaegui,D] Área de Neurociencias, Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain. [ Olascoaga,J] Servicio de Neurología, Unidad de Esclerosis Múltiple, Hospital Donostia, San Sebastián, Spain. [Urcelay,E, Ortiz,MA] Immunology Department H. Clínico S. Carlos, Instituto de Investigación Sanitaria S. Carlos (IdISSC), Madrid, Spain. [Arroyo,R] Multiple Sclerosis Unit, Neurology Department H. Clínico S. Carlos, Instituto de Investigación Sanitaria S. Carlos (IdISSC), Madrid, Spain. [Oksenberg,JR] Department of Neurology, University of California San Francisco, San Francisco, California, United States of America. [Antigüedad,A] Servicio de Neurología, Hospital de Basurto, Bilbao, Spain. [Vandenbroeck,K] IKERBASQUE, Basque Foundation for Science, Bilbao, Spain, This work was supported from the European Community’s Seventh Framework Programme [FP7/2007–2013] under grant agreement no. 212877 (UEPHA*MS, and ref. IT512-10). UEPHA*MS (No 2121877). Ministerio de Ciencia e Innovación - FEDER (SAF2009-11491) and FIS_FEDER (CP10/00526), Junta de Andalucía-FEDER (P07-CVI-02551).
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Antigens, Differentiation, T-Lymphocyte ,CD4-Positive T-Lymphocytes ,Male ,BIOCHEMISTRY AND MOLECULAR BIOLOGY ,lcsh:Medicine ,Genome-wide association study ,Polimorfismo genético ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Linkage Disequilibrium ,Phenomena and Processes::Genetic Phenomena::Genotype::Haplotypes [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,0302 clinical medicine ,Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Epidemiologic Research Design::Genome-Wide Association Study [Medical Subject Headings] ,Gene Order ,Cluster Analysis ,Cytotoxic T cell ,lcsh:Science ,Genetics ,0303 health sciences ,Multidisciplinary ,Genome-wide association ,T Cells ,Chromosome Mapping ,Genomics ,Helper 17 cells ,Neurology ,AGRICULTURAL AND BIOLOGICAL SCIENCES ,Cytokines ,Female ,Haplotipos ,Diseases::Immune System Diseases::Autoimmune Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings] ,Research Article ,Adult ,Multiple Sclerosis ,Immune Cells ,Immunology ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,White People ,Autoimmune Diseases ,Central-nervous-system ,Young Adult ,03 medical and health sciences ,Antigen ,Antigens, CD ,Humans ,SNP ,Genetic Predisposition to Disease ,Protein Interaction Domains and Motifs ,030304 developmental biology ,Inflammation ,MEDICINE ,Haplotype ,lcsh:R ,Immunity ,Timocitos ,Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic [Medical Subject Headings] ,Haplotypes ,Genetic Loci ,Spain ,Esclerosis múltiple ,estudio de asociación genómica completa ,Genetic Polymorphism ,Anatomy::Cells::Thymocytes [Medical Subject Headings] ,Clinical Immunology ,Cytokine secretion ,lcsh:Q ,Population Genetics ,CD8 ,030215 immunology ,Anti-CD6 monoclonal-antibody - Abstract
Art. nº e62376; v. 8; issue 4, 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 (Pmax(T) permutation=161024). 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+ naı¨ve cells, P = 0.0001; CD8+ naı¨ve 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., doi:10.1371/journal.pone.0062376, European Community 212877; Gobierno Vasco (Grupos de Investigacion del Sistema Universitario Vasco) IT512-10;Ministerio de Ciencia e Innovacion - FEDER SAF2009-11491;FIS_FEDER CP10/00526 ;Junta de Andalucia-FEDER P07-CVI-02551
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- 2013