Ueda, Hironori and Howson, Joanna M. M. and Esposito, Laura and Heward, Joanne and Snook, Hywel and Chamberlain, Giselle and Rainbow, Daniel B. and Hunter, Kara M. D. and Smith, Annabel N. and Di Genova, Gianfranco and Herr, Mathias H. and Dahlman, Ingrid and Payne, Felicity and Smyth, Deborah and Lowe, Christopher and Twells, Rebecca C. J. and Howlett, Sarah and Healy, Barry and Nutland, Sarah and Rance, Helen E. and Everett, Vin and Smink, Luc J. and Lam, Alex C. and Cordell, Heather J. and Walker, Neil M. and Bordin, Cristina and Hulme, John and Motzo, Costantino and Cucca, Francesco and Hess, J. Fred and Metzker, Michael L. and Rogers, Jane and Gregory, Simon and Allahabadia, Amit and Nithiyananthan, Ratnasingam and Tuomilehto Wolf, Eva and Tuomilehto, Jaakko and Bingley, Polly and Gillespie, Kathleen M. and Undlien, Dag Erik and Rønningen, Kjersti Skjold and Guja, Cristian and Ionescu Tirgoviste, Constantin and Savage, David A. and Maxwell, Alexander Peter and Carson, Dennis J. and Patterson, Christopher C. and Franklyn, Jayne A. and Clayton, David G. and Peterson, Laurence B. and Wicker, Linda S. and Todd, John A. and Gough, Stephen C. L. (2003) Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature, Vol. 423 (6939), p. 506-511. eISSN 1476-4687. Article.
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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.
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