GENETIC SUSCEPTIBILITY TO THE DEVELOPMENT OF AUTOIMMUNE-DISEASE

1. Autoimmune diseases are common conditions which appear to develop i n genetically susceptible individuals, with expression of disease bein g modified by permissive and protective environments, Familial cluster ing and data from twin studies provided the impetus for the search for putative loci, Both the candidate gene approach in population-based c ase-control studies and entire genome screening in families have helpe d identify susceptibility genes in a number of autoimmune diseases, 2, After the first genome screen in type 1 (insulin-dependent) diabetes mellitus it seems likely that most autoimmune diseases are polygenic w ith no single gene being either necessary or sufficient for disease de velopment, Of the organ-specific autoimmune diseases, genome screens h ave now been completed in insulin-dependent diabetes mellitus and mult iple sclerosis, Furthermore, the clustering of autoimmune diseases wit hin the same individuals suggests that the same genes may be involved in the different diseases, This is supported by data showing that both HLA (human leucocyte antigen:, and CTLA-4 (cytotoxic T-lymphocyte-ass ociated-4) appear to be involved in the development of insulin-depende nt diabetes mellitus and Graves' disease, 3, Genome screens have also been completed in some of the non-organ-specific autoimmune diseases i ncluding rheumatoid arthritis, inflammatory bowel disease and psoriasi s, Many candidate genes have also been investigated although these are predominantly in population-based case-control studies, 4, Substantia l progress has been made in recent years towards the identification of susceptibility loci in autoimmune diseases, The inconsistencies seen between case-control studies may largely he due to genetic mismatching between cases and controls in small datasets, Family-based associatio n studies are being increasingly used to confirm genetic linkages and help with fine mapping strategies, It will, however, require a combina tion of biology and genetics, as has been necessary with the major his tocompatibility complex in insulin-dependent diabetes mellitus, to ide ntify primary aetiological mutations.