Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

被引：2062

作者：

Sawcer, Stephen ^{[1
]}

Hellenthal, Garrett ^{[2
]}

Pirinen, Matti ^{[2
]}

Spencer, Chris C. A. ^{[2
]}

Patsopoulos, Nikolaos A. ^{[3
,4
,5
]}

Moutsianas, Loukas ^{[6
]}

Dilthey, Alexander ^{[6
]}

Su, Zhan ^{[2
]}

Freeman, Colin ^{[2
]}

Hunt, Sarah E. ^{[7
]}

Edkins, Sarah ^{[7
]}

Gray, Emma ^{[7
]}

Booth, David R. ^{[8
]}

Potter, Simon C. ^{[7
]}

Goris, An ^{[9
]}

Band, Gavin ^{[2
]}

Oturai, Annette Bang ^{[10
]}

Strange, Amy ^{[2
]}

Saarela, Janna ^{[11
]}

Bellenguez, Celine ^{[2
]}

Fontaine, Bertrand ^{[12
]}

Gillman, Matthew ^{[7
]}

Hemmer, Bernhard ^{[13
]}

Gwilliam, Rhian ^{[7
]}

Zipp, Frauke ^{[14
,15
]}

Jayakumar, Alagurevathi ^{[7
]}

Martin, Roland ^{[15
]}

Leslie, Stephen ^{[17
]}

Hawkins, Stanley ^{[18
]}

Giannoulatou, Eleni ^{[2
]}

D'alfonso, Sandra ^{[19
,20
]}

Blackburn, Hannah ^{[7
]}

Boneschi, Filippo Martinelli ^{[21
]}

Liddle, Jennifer ^{[7
]}

Harbo, Hanne F. ^{[22
,23
]}

Perez, Marc L. ^{[7
]}

Spurkland, Anne ^{[24
]}

Waller, Matthew J. ^{[7
]}

Mycko, Marcin P. ^{[25
]}

Ricketts, Michelle ^{[7
]}

Comabella, Manuel ^{[26
]}

Hammond, Naomi ^{[7
]}

Kockum, Ingrid ^{[27
]}

McCann, Owen T. ^{[7
]}

Ban, Maria ^{[1
]}

Whittaker, Pamela ^{[7
]}

Kemppinen, Anu ^{[1
]}

Weston, Paul ^{[7
]}

Hawkins, Clive ^{[28
]}

Widaa, Sara ^{[7
]}

机构：

[1] Univ Cambridge, Dept Clin Neurosci, Addenbrookes Hosp, Cambridge CB2 0QQ, England

[2] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England

[3] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Genet,Dept Med, Boston, MA 02115 USA

[4] Broad Inst Harvard Univ & Massachusetts Inst Tech, Cambridge, MA 02142 USA

[5] Brigham & Womens Hosp, Dept Neurol, Ctr Neurol Dis, Boston, MA 02115 USA

[6] Univ Oxford, Dept Stat, Oxford OX1 3TG, England

[7] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[8] Univ Sydney, Westmead Millennium Inst, Sydney, NSW 2145, Australia

[9] Katholieke Univ Leuven, Sect Expt Neurol, Lab Neuroimmunol, B-3000 Louvain, Belgium

[10] Rigshosp, Copenhagen Univ Hosp, Dept Neurol, Danish Multiple Sclerosis Ctr, DK-2100 Copenhagen, Denmark

[11] Univ Helsinki, Inst Mol Med Finland FIMM, FIN-00290 Helsinki, Finland

[12] UPMC, AP HP, INSERM UMR S CRICM 975, Dept Neurol Pitie Salpetriere, F-75013 Paris, France

[13] Tech Univ Munich, Klinikum Rechts Isar, Dept Neurol, D-81675 Munich, Germany

[14] Johannes Gutenberg Univ Mainz, Univ Med Mainz, Dept Neurol, D-55131 Mainz, Germany

[15] Max Delbrueck Ctr Mol Med, D-13092 Berlin, Germany

[16] Ctr Mol Neurobiol, Inst Neuroimmunol & Clin MS Res Inims, D-20251 Hamburg, Germany

[17] Univ Oxford, Dept Clin Pharmacol, Oxford OX3 7DQ, England

[18] Queens Univ Belfast, Belfast BT7 1NN, Antrim, North Ireland

[19] Univ Piemonte Orientale, Dept Med Sci, I-28100 Novara, Italy

[20] Univ Piemonte Orientale, IRCAD, I-28100 Novara, Italy

[21] Ist Sci San Raffaele, Dept Neurol, Inst Expt Neurol INSPE, Div Neurosci, I-20132 Milan, Italy

[22] Oslo Univ Hosp, Dept Neurol, N-0407 Oslo, Norway

[23] Univ Oslo, Dept Neurol, N-0318 Oslo, Norway

[24] Univ Oslo, Inst Basal Med Sci, N-0317 Oslo, Norway

[25] Med Univ Lodz, Lab Neuroimmunol, Dept Neurol, PL-90153 Lodz, Poland

[26] Vall dHebron Univ Hosp, Multiple Sclerosis Ctr Catalonia CEM Cat, Clin Neuroinmunol Unit, Barcelona 08035, Spain

[27] Karolinska Inst, Karolinska Univ Hosp, Ctr Mol Med CMM, Dept Clin Neurosci, SE-17176 Stockholm, Sweden

[28] Keele Univ, Sch Med, Stoke On Trent ST4 7NY, Staffs, England

[29] Univ Exeter, Peninsula Coll Med & Dent, Plymouth PL6 8BX, Devon, England

[30] Univ Plymouth, Clin Neurol Res Grp, Plymouth PL6 8BX, Devon, England

[31] Univ Wales Hosp, Dept Neurol, Cardiff CF14 4XW, S Glam, Wales

[32] Univ Calif Berkeley, Genet Epidemiol & Genom Lab, Div Epidemiol, Sch Publ Hlth, Berkeley, CA 94720 USA

[33] Kaiser Permanente No Calif Div Res, Oakland, CA 94612 USA

[34] Karolinska Inst, Inst Expt Med, S-17177 Stockholm, Sweden

[35] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[36] IRCCS, Neurol Inst C Mondino, I-27100 Pavia, Italy

[37] Walton Ctr Neurol & Neurosurg, Liverpool L7 9LJ, Merseyside, England

[38] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[39] INSERM, U1043, F-31059 Toulouse, France

[40] Hop Purpan, F-31059 Toulouse, France

[41] Griffith Univ, Sch Med, Gold Coast, Qld 4222, Australia

[42] Univ Melbourne, Florey Neurosci Inst, Melbourne, Vic 3010, Australia

[43] Royal Melbourne Hosp, Parkville, Vic 3050, Australia

[44] Monash Univ, Box Hill Hosp, Clayton, Vic 3800, Australia

[45] Univ Melbourne, Dept Med, RMH Cluster, Melbourne, Vic 3010, Australia

[46] Osped Civili Brescia, Dept Neurol, Multiple Sclerosis Ctr, I-25018 Brescia, Italy

[47] Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Perth, WA 6009, Australia

[48] Univ Turin, AOU San Giovanni Battista, Dept Neurosci, I-10126 Turin, Italy

[49] Univ Paris 11, INSERM, U669, F-94800 Villejuif, France

[50] Univ Newcastle, Callaghan, NSW 2308, Australia

来源：

NATURE | 2011年 / 476卷 / 7359期

基金：

澳大利亚研究理事会; 芬兰科学院; 英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; HETEROGENEITY; HAPLOTYPES; VARIANTS; ALLELES;

D O I：

10.1038/nature10251

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability(1). Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals(2,3), and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk(4). Modestly powered genome-wide association studies (GWAS)(5-10) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility(11). Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

引用

页码：214 / 219

页数：6

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