Complex interaction between HLA DR and DQ in conferring risk for childhood type 1 diabetes.

Type 1 (insulin-dependent) diabetes mellitus is associated with HLA DR and DQ factors, but the primary risk alleles are difficult to identify because recombination events are rare in the DQ-DR region. The risk of HLA genotypes for type 1 diabetes was therefore studied in more than 420 incident new onset, population-based type 1 diabetes children and 340 age, sex and geographically matched controls from Sweden. A stepwise approach was used to analyse risk by relative and absolute risks, stratification analysis and the predispositional allele test. The strongest relative and absolute risks were observed for DQB102-DQA10501/DQB10302-DQA10301 heterozygotes (AR 1/46, P < 0.001) or the simultaneous presence of both DRB103 and DQB10302 (AR 1/52, P < 0.001). Stratification analysis showed that DQB10302 was more frequent among DRB104 patients than DRB104 controls (P < 0.001), while DRB103 was more frequent among both DQA10501 (P < 0.001) and DQB102 (P < 0.001) patients than respective controls. The predispositional allele test indicated that DRB103 (P < 0.001) would be the predominant risk factor on the DRB103-DQA10501-DQB102 haplotype. In contrast, although DQB10302 (P < 0.001) would be the predominant risk factor on the DRB104-DQA10301-DQB10302 haplotype, the predispositional allele test also showed that DRB10401, but no other DRB104 subtype, had an additive risk to that of DQB10302 (P < 0.002). It is concluded that the association between type 1 diabetes and HLA is due to a complex interaction between DR and DQ since (1) DRB103 was more strongly associated with the disease than DQA10501-DQB102 and (2) DRB10401 had an additive effect to DQB10302. The data from this population-based investigation suggest an independent role of DR in the risk of developing type 1 diabetes, perhaps by providing diseases-promoting transcomplementation molecules.