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.
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Acknowledgements
We thank the Juvenile Diabetes Research Foundation (JDRF), the Wellcome Trust, NovoNordisk, Novo Nordisk Foundation, the Academy of Finland, The Sigrid Juselius Foundation, Diabetes UK and the Medical Research Council for financial support. H.U. was a Wellcome Trust Travelling Fellow and R.N. is a West Midlands Regional Health Authority Sheldon Medical Research Fellow. The availability of NOD congenic mice through the Taconic Farms Emerging Models Program has been made possible and is supported by grants from the Merck Genome Research Institute, NIAID and the JDRF. We gratefully acknowledge the participation of all patients, controls and family members, including provision of samples from T1D families from the Human Biological Data Interchange and Diabetes UK repositories, and sample collections by The Norwegian Study Group for Childhood, preparation of manuscript materials by J. Brown and T. Thorn, and review of the manuscript by C. Rudd, C. Nathan, M. Bobrow, P. Lyons, R. Glynne, C. Goodnow, J. Trowsdale, N. Proudfoot, T. Merriman, N. Hastie and D. Sansom.
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Supplementary information
41586_2003_BFnature01621_MOESM1_ESM.pdf
Supplementary Information A: Description for CD28-CTLA4-ICOS region of (a) genomic informatics methods and results, including human-mouse comparative sequence analysis and gene annotation, (b) details of the single nucleotide polymorphisms – their sequences and genotyping QC results and (c) methods and results from the analysis of the transcription of the CTLA-4 gene. (PDF 370 kb)
41586_2003_BFnature01621_MOESM2_ESM.pdf
Supplementary Information B: Intermarker linkage disequilibrium analysis for the 108 single nucleotide polymorphisms studied in the CD28-CTLA4-ICOS region and a detailed description of the fine mapping approach using logistic regression analyses in Graves’ disease and in type 1 diabetes, including single point and haplotype results. (PDF 210 kb)
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Ueda, H., Howson, J., Esposito, L. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003). https://doi.org/10.1038/nature01621
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DOI: https://doi.org/10.1038/nature01621
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