Endocrine Abstracts (2004) 7 S28

Gene linkage and association studies in autoimmune thyroid disease

SCL Gough


Division of Medical Sciences; Department of Medicine; University of Birmingham; Birmingham; West Midlands; UK.


Autoimmune thyroid disease (AITD) clusters in families pointing, at least in part, to a genetic basis for disease. Subjects with AITD and other family members also have an increased risk for the development of other autoimmune diseases such as type 1 diabetes (TID) and rheumatoid arthritis suggesting the involvement of general autoimmunity genes. In common with other autoimmune diseases the HLA region was the first cluster of genes to be reported to be associated with AITD. More recent studies showing that specific HLA class II genes including DRB1, are acting as primary disease determinants for AITD, have also implicated specific amino acid sequences within peptide binding pockets as leading potentially to increased autoantigen presentation and binding. Recently, disease susceptibility has also been mapped to a non-coding 6.1 kb region of the CTLA-4 gene, an important negative regulator of the immune system. As the HLA and CTLA-4 gene regions appear to collectively contribute to about half of the inheritance of AITD, a large number of both candidate gene studies and genome wide searches have been performed to identify both disease specific and general autoimmunity genes. To date however, novel loci await replication and confirmation. These results suggest an initial overestimation of the contribution of individual genes to disease and that the genetic basis to AITD is the result of both common and rare alleles (mixture of common-disease common variant-multiple rare variant hypothesis). The way ahead therefore rests with our ability to test for DNA variants in a large number of candidate genes in adequately powered data sets. The emergence of more detailed maps of the human genome supported by recently funded national DNA resources will facilitate the discovery of novel loci, helping us to explain the genetic basis to AITD and causes of autoimunity in general.

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