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

Nature 2003 May 30;423(6939):506-11. Epub 2003 Apr 30.

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.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature01621DOI Listing
May 2003
62 Reads

Publication Analysis

Top Keywords

type diabetes
8
splice form
8
autoimmune disorders
8
autoimmune
5
graves' disease
4
disease autoimmune
4
disorders graves'
4
diabetes susceptibility
4
risk common
4
common autoimmune
4
risk identify
4
mouse model
4
soluble alternative
4
hypothyroidism type
4
model type
4
autoimmune hypothyroidism
4
determinants risk
4
encoding molecule
4
cd80/cd86 ligand-binding
4
immune system--as
4

Similar Publications