Genetic susceptibility to type I diabetes: a review

There is evidence that Type I diabetes is a genetically and environmentally determined disease. Among the genetic influences the HLA system appears to play a dominant role. HLA-DQ has been strongly implicated as the primary responsible locus by the recent discovery that position 57 in the polymorphic first domain of the DQB chain appears to be a critical residue in conferring susceptibility. DQB products which contain the negatively charged amino acid aspartate at this position are protective while those containing the neutral valine, serine or alanine are susceptibility molecules. This discovery has served to explain, in a reductionist manner, some of the previously described HLA associations seen with diabetes. However, there are clear exceptions to the position 57 hypothesis which appears to explain some, but not all, of the HLA risk associated with this disease. Evidence is accumulating that the HLA contribution to diabetes susceptibility is heterogeneous, resulting in the identification of patient subgroups. When heterogeneity, revealed by studying non-HLA genes such as Gm, T-cell receptor and interleukin, are superimposed on HLA genetic risk, further complexity is likely to arise. The definition of patient subgroups defined by genetic profiles will be required in order to study the contribution of environmental factors effectively.