Increased Frequency of the HLA-DRB1*04:04-DQA1*03-DQB1*03:02 Haplotype among HLA-DQB1*06:02 Positive Children with Type 1 Diabetes
HLA DR-DQ haplotypes largely define genetic susceptibility to type 1 diabetes (T1D). The DQB1*06:02 positive haplotype (DR15-DQ602) common in subjects of European ancestry is very rare among children with T1D. Among 4490 children with T1D in the Finnish Pediatric Diabetes Register 57 (1.3%) cases with DQB1*06:02 were identified in comparison to 26.1% of affected family-based association controls. There was no difference 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 the 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 of 57 (47.4%) children compared to only 797/4433 (18.0%) among DQB1*06:02 negative cases (P<0.001, Chi-square test). The other common risk associated haplotypes, the DRB1*04:01-DQA1*03-DQB1*03:02 and (DR3)-DQA1*05-DQB1*02 were less prevalent in DQB1*06:02 positive than DQB1*06:02 negative children (P<0.001). HLA-B allele frequencies did not differ between DQB1*06:02 haplotypes in children with T1D and controls and neither in DRB1*04:04-DQA1*03-DQB1*03:02 haplotypes of DQB1*06:02 positive and negative T1D children. The increased frequency of DRB1*04:04 allele among DQB1*06:02 positive cases may indicate preferential ability of the DR404 molecule to present islet antigen epitopes despite of the competition by DQ602. ARTICLE HIGHLIGHTS · The common HLA-DQB1*06:02 allele is strongly protective against type 1 diabetes although few DQB1*06:02 positive cases have been found. · We compared the distribution of the second class II haplotypes in DQB1*06:02 positive children with type 1 diabetes to haplotypes found in in other children with type 1 diabetes. · HLA-DRB1*04:04-DQA1*03-DQB1*03:02 was the most common second haplotype in DQB1*06:02 positive diabetic children whereas DRB1*04:01-DQA1*03-DQB1*03:02 was most frequent in other children with type 1 diabetes. · The finding suggests that binding of 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.