Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Ueda, Hironori
Howson, Joanna M. M.
Esposito, Laura
Heward, Joanne
Snook, Hywel
Chamberlain, Giselle
Rainbow, Daniel B.
Hunter, Kara M. D.
Smith, Annabel N.
Di Genova, Gianfranco
Herr, Mathias H.
Dahlman, Ingrid
Payne, Felicity
Smyth, Deborah
Lowe, Christopher
Twells, Rebecca C. J.
Howlett, Sarah
Healy, Barry
Nutland, Sarah
Rance, Helen E.
Everett, Vin
Smink, Luc J.
Lam, Alex C.
Cordell, Heather J.
Walker, Neil M.
Bordin, Cristina
Hulme, John
Motzo, Costantino
Cucca, Francesco
Hess, J. Fred
Metzker, Michael L.
Rogers, Jane
Gregory, Simon
Allahabadia, Amit
Nithiyananthan, Ratnasingam
Tuomilehto-Wolf, Eva
Tuomilehto, Jaakko
Bingley, Polly
Gillespie, Kathleen M.
Undlien, Dag E.
Rønningen, Kjersti S.
Guja, Cristian
Ionescu-Tîrgovişte, Constantin
Savage, David A.
Maxwell, A. Peter
Carson, Dennis J.
Patterson, Chris C.
Franklyn, Jayne A.
Clayton, David G.
Peterson, Laurence B.
Wicker, Linda S.
Todd, John A.
Gough, Stephen C. L.

¹Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge, CB2 2XY, UK; ²Division of Medical Sciences, University of Birmingham, Birmingham, B15 2TT, UK; ³Dipartimento di Scienze Biomediche e Biotecnologie, Universita di Cagliari, Cagliari, Italy; ⁴Merck Research Laboratories, West Point, Pennsylvania 19486, USA; ⁵Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK; ⁶Diabetes and Genetic Epidemiology Unit, National Public Health Institute, University of Helsinki, Helsinki, Finland; ⁷Department of Public Health, University of Helsinki, Helsinki, Finland; ⁸Diabetes and Metabolism Unit, Division of Medicine, University of Bristol, Bristol, BS10 5NG, UK; ⁹Institute of Immunology, Rikshospitalet University Hospital and Institute of Medical Genetics, Ulleval University Hospital, University of Oslo, Oslo, Norway; ¹⁰Laboratory of Molecular Epidemiology, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway; ¹¹Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases 'N. Paulescu', Bucharest, Romania; ¹²Department of Medical Genetics, Queen's University Belfast, Belfast City Hospital, Belfast, BT9 7AB, UK; ¹³Regional Nephrology Unit, Belfast City Hospital, Belfast, BT9 7AB, UK; ¹⁴Department of Child Health, Queen's University Belfast, Belfast, BT12 6BJ, UK; ¹⁵Department of Epidemiology and Public Health, Queen's University Belfast, Belfast, BT12 6BJ, UK; ¹⁶Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.

*These authors contributed equally to this work

† Present addresses: HIT Group, Tenovus Research Laboratories, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK (G.D.G.); Department of Paediatrics, Otto-Heubner-Centrum, Charité, Humboldt-University of Berlin, Germany (M.H.H.); Karolinska Institute, Department of Medicine, Huddinge University Hospital, Stockholm, Sweden (I.D.); Hutchison/MRC Research Centre, Hills Road, Cambridge, CB2 2XZ, UK (C.B.); Department of Molecular & Human Genetics, Baylor Genome Sequencing Center, Baylor College of Medicine, N1409, One Baylor Plaza, Houston, Texas 77030, USA (M.L.M.); Division of Clinical Sciences, University of Sheffield, Northern General Hospital, Sheffield, S5 7AU, UK (A.A.); Institute of Medical Genetics, University of Oslo, N-0315 Oslo, Norway (D.E.U.).

Received 23 December 2002; accepted 3 April 2003; doi:10.1038/nature01621.

Published online 30 April 2003.

Supplementary Information accompanies the paper on www.nature.com/nature.

Correspondence and requests for materials should be addressed to J.A.T.

([email protected]) or L.S.W. ([email protected]).

Nature 423(6939):p 506-511, May 29, 2003.

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)-which encodes a vital negative regulatory molecule of the immune system-as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3′ region ofCTLA4,the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form ofCTLA4.In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations ofCTLA4contributing to autoimmune tissue destruction.