HLA-DQβ Sequence Polymorphism and Genetic Susceptibility to IDDM

The analysis of HLA-DQβ nucleotide sequence polymorphism in insulin-dependent diabetes mellitus (IDDM) patients and control subjects suggests a role for the DQβ-chain in genetic susceptibility. Sequence determination and oligonucleotide hybridization was carried out on enzymatically amplified DNA from various HLA-DR-typed individuals, including the rare class of DR2⁺ patients. In the analysis of DQβ variation in DR4, DRw6, and DR2 haplotypes, a correlation was observed between the presence of the negatively charged residue Asp at position 57 and low susceptibility and the presence of an Ala (DR4), Val (DRw6), or Ser (DR2) and higher susceptibility. However, important exceptions to this pattern have been identified in the analysis of heterozygous DR1/4 IDDM patients. In these individuals, susceptibility appears to correlate with specific DRβ1 alleles (Dw4) on the DR4 haplotype, rather than with the DQβ allele (DQB3.2) that contains Ala at position 57. The DQβ alleles found in some Chinese IDDM patients also proved discordant with the position-57 correlations. Thus, although there is a general correlation between the residue at position 57 of the DQβ-chain and IDDM susceptibility, these data do not support the notion that Asp 57 confers complete resistance or protection to IDDM. In general, these results suggest that IDDM susceptibility is conferred by specific combinations of DQβ and DRp sequences.