Class II HLA DNA polymorphisms in Type 1 (insulin-dependent) diabetic patients of North Indian origin

Abstract

Genetic associations with Type 1 (insulin-dependent) diabetes may be primary or secondary to linkage disequilibrium. Studies of different racial groups should allow these to be distinguished. We have reported that Type 1 diabetes is associated with HLA-DR3 and -DR4 in subjects of North Indian (Punjab) origin and now present the results of a study of HLA class II DNA polymorphisms in this group and in white caucasoid subjects. DR4 in North Indian Type 1 diabetic patients was associated with DQ beta and DX alpha DNA polymorphisms identical to those found in DR4-positive white caucasoid patients. This DQ beta/DX alpha pattern was increased in frequency in North Indian diabetic patients vs control subjects (33.3% vs 8.5%, p less than 0.001, relative risk = 5.12 (95% confidence limits: 1.96-13.4)). A DQ beta polymorphism with very low relative risk for Type 1 diabetes in white caucasoid subjects was also markedly reduced in North Indian diabetic patients vs control subjects (2.3% vs 24.7%, p less than 0.02, relative risk = 0.10 (95% confidence limits: 0.02-0.46)). This pattern was associated with DR2 in white caucasoid subjects, but with DRw6 in North Indians. A DR3-associated DR beta polymorphism was markedly increased in North Indian diabetic patients vs control subjects (90.2% vs 40.7%, p less than 10(-6), relative risk = 12.1 (95% confidence limits: 4.32-33.9)). The DQ subregion may be a primary site of genetic influence on susceptibility to Type 1 diabetes. Further studies in different racial groups will clarify the HLA associations of Type 1 diabetes.

Genetic analysis of susceptibility to Type 1 diabetes

“…The DR1 association is consistently found in caucasians. Significant DR1 effects in Type 1 diabetes have not been confirmed in studies of other ethnic groups [27,28,50,68,95]. An explanation of this may be that the number of patients studied has not been large enough to detect a weak, but positive association.…”

“…A DQB1 RFLP that marks resistance to Type 1 diabetes on DR2 haplotypes also correlates with resistance on DR6 haplotypes [27,28,50,94,95]. As described above for putative susceptibility alleles of DQA1 and DQB1, DQassociated sequences correlate with resistance across ethnic group variations in haplotypes and also in the presence of different DRB1 alleles.…”

“…A3 and DQw2 also occur on race-specific, black DR5 [56] and DR9 [28] haplotypes, both of which predispose to disease. Allelic sequencing of a diabetogenic black DR9 haplotype showed that the neutral allele DQw9 (Asp57) is replaced with DQw2 (Fig 4; [115 Finally, it is noted that the DR3/4 effect is not as strong in blacks as it is in caucasians [27,126].…”

“…Other DR2 haplotypes encode Asp57 DQ ~ chains. RFLP analysis also maps susceptibility and reistance to the DQ subregion in different ethnic groups [28,50,68,95].…”

DQA1*Arg52, DQB1*nonAsp57, and DRB1*04 Genotypes in Chinese Children with Insulin-Dependent Diabetes mellitus

“…Todd et al [7] later found that IDDM susceptibility was associated with a nonaspartic acid residue present at position 57 of the DQß chain. Subsequently, arginine at position 52 of the DQ· chain was found to confer marked susceptibility to IDDM [8][9][10].…”