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.
journal_name
Naturejournal_title
Natureauthors
Ueda H,Howson JM,Esposito L,Heward J,Snook H,Chamberlain G,Rainbow DB,Hunter KM,Smith AN,Di Genova G,Herr MH,Dahlman I,Payne F,Smyth D,Lowe C,Twells RC,Howlett S,Healy B,Nutland S,Rance HE,Everett V,Smink LJ,Ldoi
10.1038/nature01621keywords:
subject
Has Abstractpub_date
2003-05-29 00:00:00pages
506-11issue
6939eissn
0028-0836issn
1476-4687pii
nature01621journal_volume
423pub_type
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