DIFFERENT CONTRIBUTION OF HLA-DR AND HLA-DQ GENES IN SUSCEPTIBILITY AND RESISTANCE TO INSULIN-DEPENDENT DIABETES-MELLITUS (IDDM)

Previous studies have indicated that certain alleles of HLA-DR and -DQ genes were strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM), and the role of DQ molecul e in IDDM has been suggested. To further clarify the association of DQ alleles with IDDM, we determined the nucleotide sequences of full-len gth cDNA from 13 DQA1 alleles and 14 DQB1 alleles. The sequencing anal ysis revealed sequence polymorphisms outside the hypervariable region of DQ genes. We then analyzed the DQA1 and DQB1 polymorphisms along wi th that of DRB genes in 86 B-lymphoblastoid cell lines (B-LCLs) from v arious ethnic groups and in healthy unrelated Japanese and Norwegian i ndividuals. The allelic and haplotypic distributions in each populatio n revealed the characteristic haplotypic formation in the HLA class II region. HLA genes in 139 Japanese and 100 Norwegian IDDM patients wer e analyzed. DQB10301 was negatively associated with IDDM in both ethn ic groups, irrespective of associated DRB1 and DQA1 alleles. In DQB10 302 positive populations, which represented a positive association wit h IDDM in both ethnic groups, DRB10401, *0404, *0802 haplotypes incre ased in the patients, whereas DRB10406 haplotype decreased. Consideri ng about the hierarchy in DRB1 alleles with IDDM susceptibility (DRBl 0401>0404>*0403 in Norwegian and DRB1*0802>*0403>*0406 in Japanese), the genetic predisposition to IDDM is suggested to be defined by the c ombination of DR-associated susceptibility and DQ-associated susceptib ility and by the DQ-associated resistance which is a dominant genetic trait.