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

Hironori Ueda, Joanna M. M. Howson, Laura Esposito, Joanne Heward, Snook, Giselle Chamberlain, Daniel B. Rainbow, Kara M. D. Hunter, Annabel N. Smith, Gianfranco Di Genova, Mathias H. Herr, Ingrid Dahlman, Felicity Payne, Deborah Smyth, Christopher Lowe, Rebecca C. J. Twells, Sarah Howlett, Barry Healy, Sarah Nutland, Helen E. Rance, Vin Everett, Luc J. Smink, Alex C. Lam, Heather J. Cordell, Neil M. Walker, Cristina Bordin, John Hulme, Costantino Motzo, Francesco Cucca, J. Fred Hess, Michael L. Metzker, Jane Rogers, Simon Gregory, Amit Allahabadia, Ratnasingam Nithiyananthan, Eva Tuomilehto-Wolf, Jaakko Tuomilehto, Polly Bingley, Kathleen M. Gillespie, Dag E. Undlien, Kjersti S. Rønningen, Cristian Guja, Constantin Ionescu-Tîrgovişte, David A. Savage, A. Peter Maxwell, Dennis J. Carson, Chris C. Patterson, Jayne A. Franklyn, David G. Clayton, Laurence B. Peterson, Linda S. Wicker (), John A. Todd () and Stephen C. L. Gough
Additional contact information
Hironori Ueda: University of Cambridge, Wellcome Trust/MRC Building
Joanna M. M. Howson: University of Cambridge, Wellcome Trust/MRC Building
Laura Esposito: University of Cambridge, Wellcome Trust/MRC Building
Joanne Heward: University of Birmingham
Snook: University of Cambridge, Wellcome Trust/MRC Building
Giselle Chamberlain: University of Cambridge, Wellcome Trust/MRC Building
Daniel B. Rainbow: University of Cambridge, Wellcome Trust/MRC Building
Kara M. D. Hunter: University of Cambridge, Wellcome Trust/MRC Building
Annabel N. Smith: University of Cambridge, Wellcome Trust/MRC Building
Gianfranco Di Genova: University of Cambridge, Wellcome Trust/MRC Building
Mathias H. Herr: University of Cambridge, Wellcome Trust/MRC Building
Ingrid Dahlman: University of Cambridge, Wellcome Trust/MRC Building
Felicity Payne: Universita di Cagliari
Deborah Smyth: University of Cambridge, Wellcome Trust/MRC Building
Christopher Lowe: University of Cambridge, Wellcome Trust/MRC Building
Rebecca C. J. Twells: University of Cambridge, Wellcome Trust/MRC Building
Sarah Howlett: University of Cambridge, Wellcome Trust/MRC Building
Barry Healy: University of Cambridge, Wellcome Trust/MRC Building
Sarah Nutland: University of Cambridge, Wellcome Trust/MRC Building
Helen E. Rance: University of Cambridge, Wellcome Trust/MRC Building
Vin Everett: University of Cambridge, Wellcome Trust/MRC Building
Luc J. Smink: University of Cambridge, Wellcome Trust/MRC Building
Alex C. Lam: University of Cambridge, Wellcome Trust/MRC Building
Heather J. Cordell: University of Cambridge, Wellcome Trust/MRC Building
Neil M. Walker: University of Cambridge, Wellcome Trust/MRC Building
Cristina Bordin: University of Cambridge, Wellcome Trust/MRC Building
John Hulme: University of Cambridge, Wellcome Trust/MRC Building
Costantino Motzo: Universita di Cagliari
Francesco Cucca: Universita di Cagliari
J. Fred Hess: Merck Research Laboratories
Michael L. Metzker: Merck Research Laboratories
Jane Rogers: Wellcome Trust Sanger Institute
Simon Gregory: University of Helsinki
Amit Allahabadia: University of Birmingham
Ratnasingam Nithiyananthan: University of Birmingham
Eva Tuomilehto-Wolf: University of Helsinki
Jaakko Tuomilehto: University of Helsinki
Polly Bingley: University of Bristol
Kathleen M. Gillespie: University of Bristol
Dag E. Undlien: Rikshospitalet University Hospital and Institute of Medical Genetics, Ulleval University Hospital, University of Oslo
Kjersti S. Rønningen: Norwegian Institute of Public Health
Cristian Guja: Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases ‘N. Paulescu’
Constantin Ionescu-Tîrgovişte: Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases ‘N. Paulescu’
David A. Savage: Queen's University Belfast, Belfast City Hospital
A. Peter Maxwell: Belfast City Hospital
Dennis J. Carson: Queen's University Belfast
Chris C. Patterson: Queen's University Belfast
Jayne A. Franklyn: University of Birmingham
David G. Clayton: University of Cambridge, Wellcome Trust/MRC Building
Laurence B. Peterson: Merck Research Laboratories
Linda S. Wicker: University of Cambridge, Wellcome Trust/MRC Building
John A. Todd: University of Cambridge, Wellcome Trust/MRC Building
Stephen C. L. Gough: University of Birmingham

Nature, 2003, vol. 423, issue 6939, 506-511

Abstract: 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.

Date: 2003
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DOI: 10.1038/nature01621

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