1. Juvenile 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;
2. Division of Medical Sciences, University of Birmingham, Birmingham, B15 2TT, UK;
3. Dipartimento di Scienze Biomediche e Biotecnologie, Universita di Cagliari, Cagliari, Italy;
4. Merck Research Laboratories, West Point, Pennsylvania 19486, USA;
5. Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK;
6. Diabetes and Genetic Epidemiology Unit, National Public Health Institute, University of Helsinki, Helsinki, Finland;
7. Department of Public Health, University of Helsinki, Helsinki, Finland;
8. Diabetes and Metabolism Unit, Division of Medicine, University of Bristol, Bristol, BS10 5NG, UK;
9. Institute of Immunology, Rikshospitalet University Hospital and Institute of Medical Genetics, Ulleval University Hospital, University of Oslo, Oslo, Norway;
10. Laboratory of Molecular Epidemiology, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway;
11. Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases 'N. Paulescu', Bucharest, Romania;
12. Department of Medical Genetics, Queen's University Belfast, Belfast City Hospital, Belfast, BT9 7AB, UK;
13. Regional Nephrology Unit, Belfast City Hospital, Belfast, BT9 7AB, UK;
14. Department of Child Health, Queen's University Belfast, Belfast, BT12 6BJ, UK;
15. Department of Epidemiology and Public Health, Queen's University Belfast, Belfast, BT12 6BJ, UK;
16. Department of Pharmacology, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
17. 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.).
18. These authors contributed equally to this work

Correspondence to: Linda S. Wicker¹John A. Todd¹ Correspondence and requests for materials should be addressed to J.A.T. (Email: john.todd@cimr.cam.ac.uk) or L.S.W. (Email: linda.wicker@cimr.cam.ac.uk).

Abstract

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 of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. 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 of CTLA4 contributing to autoimmune tissue destruction.