The Role of Genetic Predisposition to Type I (Insulin-Dependent) Diabetes Mellitus

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Abstract
The aetiology of insulin-dependent diabetes (IODM) involves genetic predisposition, a major component of which has been mapped in the HLA complex, near to or identical with genes encoding class II molecules. In Caucasian populations IDDM is strongly associated with the serologically defined HLA-DR3 and DR4 antigens, which are widely recognised as markers of susceptibility. The particularly high risk of DR3/DR4 heterozygotes suggests that susceptibility is determined by two genes acting synergistically. The development of recombinant DNA technology has allowed a finer description of the class II region and provided evidence that DQ rather than DR determinants may primarily influence IDDM susceptibility. The search for specific structural changes of the DQA and DQB genes has shown that susceptibility correlates with the absence of aspartic acid at position 57 on the DQβ chain (DQβ 57 Asp—) and/or the presence of arginine at position 52 on the DQα chain (DQα 52 Arg+). In Caucasians the formation of a putative DQ susceptibility molecule (DQα 52 Arg+, DQβ 57 Asp−) accounts best for the disease associations when transcomplementation molecules consisting of DQα and β chains encoded by different haplotypes are postulated to explain the excess risk of heterozygotes. The HLA-IDDM associations in the Japanese, however, are not explained by this model. These and other unresolved questions indicate that other residues of the DQα and β chains or other class II molecules (DRβ chains), as well as non-MHC genes, may also contribute to the susceptibility.