Complex interaction between HLA DR and DO in conferring risk for childhoodtype 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 genotype s for type 1 diabetes was therefore studied in more than 420 incident new o nset, population-based type 1 diabetes children and 340 age, sex and geogra phically matched controls from Sweden. A stepwise approach was used to anal yse risk by relative and absolute risks, stratification analysis and the pr edispositional allele test. The strongest relative and absolute risks were observed for DQB1*02-DQA1*0501/DQB1*'0302-DQA1*0301 heterozygotes (AR 1/46, P < 0.001) or the simultaneous presence of both DRB1*03 and DQB1*0302 (AR 1/52, P < 0.001). Stratification analysis showed that DQB1*0302 was more fr equent among DRB1*04 patients than DRB1*04 controls (P < 0.001), while DRB1 *03 was more frequent among both DQA1*0501 (P < 0.001) and DQB1*02 (P < 0.0 01) patients than respective controls. The predispositional allele test ind icated that DRB1*03 (P < 0.001) would be the predominant risk factor on the DRB1*03-DQA1*0501-DQB1*02 haplotype. In contrast, although DQB1*0302 (P < 0.001) would be the pre dominant risk factor on the DRB1*04-DQA1*0301-DQB1* 0302 haplotype, the predispositional allele test also showed that DRB1*0401 , but no other DRB1*04 subtype, had an additive risk to that of DQB1*0302 ( P < 0.002). It is concluded that the association between type 1 diabetes an d HLA is due to a complex interaction between DR and DQ since (1) DRB1*03 w as more strongly associated with the disease than DQA1*0501-DQB1*02 and (2) DRB1*0401 had an additive effect to DQB1*0302. The data from this populati on-based investigation suggest an independent role of DR in the risk of dev eloping type 1 diabetes, perhaps by providing diseases-promoting transcompl ementation molecules.