HLA-DR/DQ haplotypes largely define genetic susceptibility to type 1 diabetes (T1D). The DQB1*06:02-positive haplotype (DR15-DQ602) common in individuals of European ancestry is very rare among children with T1D. Among 4,490 children with T1D in the Finnish Pediatric Diabetes Register, 57 (1.3%) case patients with DQB1*06:02 were identified, in comparison with 26.1% of affected family-based association control participants. There were no differences between DQB1*06:02-positive and -negative children with T1D regarding sex, age, islet autoantibody distribution, or autoantibody levels, but significant differences were seen in the frequency of second class II HLA haplotypes. The most prevalent haplotype present with DQB1*06:02 was DRB1*04:04-DQA1*03-DQB1*03:02, which was found in 27 (47.4%) of 57 children, compared with only 797 (18.0%) of 4,433 among DQB1*06:02-negative case patients (P < 0.001 by χ2 test). The other common risk-associated haplotypes, DRB1*04:01-DQA1*03-DQB1*03:02 and (DR3)-DQA1*05-DQB1*02, were less prevalent in DQB1*06:02-positive versus DQB1*06:02-negative children (P < 0.001). HLA-B allele frequencies did not differ by DQB1*06:02 haplotype between children with T1D and control participants or by DRB1*04:04-DQA1*03-DQB1*03:02 haplotype between DQB1*06:02-positive and -negative children with T1D. The increased frequency of the DRB1*04:04 allele among DQB1*06:02-positive case patients may indicate a preferential ability of the DR404 molecule to present islet antigen epitopes despite competition by DQ602.
Article Highlights
- The common HLA-DQB1*06:02 allele is strongly protective against type 1 diabetes (T1D), although few DQB1*06:02-positive individuals have been found.
- We compared the distribution of the second class II haplotypes in DQB1*06:02-positive children with T1D with the distribution of haplotypes found in in other children with T1D.
- HLA-DRB1*04:04-DQA1*03-DQB1*03:02 was the most common second haplotype in DQB1*06:02-positive children with T1D, whereas DRB1*04:01-DQA1*03-DQB1*03:02 was most frequent in other children with T1D.
- This finding suggests that the islet-specific epitopes presented by DRB1*04:04 can more efficiently avoid binding to DQB1*06:02 than epitopes presented by other risk-associated haplotypes.
