Molecular biology of the HLA system in insulin-dependent diabetes mellitus

Genetic studies indicate that the IDDM susceptibility genes in the HLA region are closely linked to the DR3 and DR4 specificities; however, these specificities do not define the actual susceptibility genes. Molecular studies confirm this hypothesis by demonstrating restriction fragment length polymorphism between DNA's of identical DR specificities and thereby separating the DR haplotypes into those strongly or weakly associated with IDDM. Further studies at the nucleotide sequence level demonstrate further heterogeneity, with DR4 being associated with at least three different DQ beta genes and five different genes of the DR beta-1 locus. However, the majority of these subtypes are now recognized either serologically or by T-cell responses in mixed lymphocyte cultures. Furthermore, the sequences associated with IDDM are those most commonly found in DR4 individuals, ie, Dw4 and DQw3.2. Clearly, these and other class II genes must be studied for additional DNA polymorphism and their relevance for IDDM. For example, the DX alpha, 2.1-kb Taql polymorphism shows a stronger correlation with IDDM than DR3. However, it is not even known if the DX alpha genes are expressed. In addition, little is known of the DQ beta and DR beta genes associated with different DR3-associated haplotypes. Furthermore, an IDDM susceptibility gene may contain important differences in flanking or intron sequences controlling expression of these genes. The methods of recombinant DNA technology are enabling these unanswered questions to be addressed.