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

H Ueda, Joanne King, JMM Howson, L Esposito, H Snook, G Chamberlain, DB Rainbow, KMD Hunter, A Smith, G Di Genova, MH Herr, I Dahlman, F Payne, D Smyth, D Lowe, RC Twells, S Howlett, B Healy, S Nutland, HE RanceV Everett, LJ Smink, Alison Lam, HJ Cordell, NM Walker, C Bordin, Jonathan Hulme, C Motzo, F Cucca, JF Hess, ML Metzker, J Rogers, S Gregory, Amit Allahabadia, Ratnasingam Nithiyananthan, E Tuomilehto-Wolf, J Tuomilehto, P Bingley, KM Gillespie, DE Undlien, KS Ronningen, C Guja, C Ionescu-Tirgoviste, DA Savage, AP Maxwell, DJ Carson, CC Patterson, Jayne Franklyn, DG Clayton, LB Peterson, LS Wicker, JA Todd, Stephen Gough

Research output: Contribution to journalArticle

1738 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)506-511
Number of pages6
Issue number6939
Early online date30 Apr 2003
Publication statusPublished - 29 May 2003


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