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To assess the effect of Asian-specific HLA haplotypes on susceptibility to type 1 diabetes, we investigated the association of genotypic combinations of DRB1-DQB1 haplotypes with susceptibility to type 1 diabetes. We studied 132 Japanese patients with type 1 diabetes and 157 control subjects, along with 67 Korean patients and 109 control subjects. DRBI*0405-DQBI *0401 and DRB1*0901-DQB1*0303 were confirmed to be two major susceptible HLA haplotypes in the Japanese population. The frequencies of heterozygotes and homozygotes with DRB1*0405-DQB1*0401 were similarly higher in patients than in control subjects (homozygotes, 543% vs. 3.8%; heterozygotes, 48.5% vs. 26.1%). In contrast, homozygotes, but not heterozygotes, with DRB1*0901-DQB1*0303 were more frequent in patients with type 1 diabetes than in control subjects (homozygotes, 12.9% vs. 0.6%; heterozygotes, 22.0% vs. 24.8%). A similar tendency was also observed in the Korean population. In multiple logistic regression analysis, DRB1*0405-DQB1*0401 fitted a dominant model and DRB1*0901-DQB1*0303 fitted a recessive model. These data, which indicate that the contribution of "LA haplotypes to the genetic susceptibility to type 1 diabetes differs depending on the genotypic combination of HLA haplotypes, suggest the importance of extensive analysis of genotypes in studies on HLA and disease association in general. Diabetes 51:545-551, 2002
AIC, Akaike's information criterion; MHC, major histocompatibility complex; OR, odds ratio; Pc, corrected P value.
Previous studies suggested that the DRB1*0405DQB1*0401 haplotype might confer a strong predisposing effect to type 1 diabetes in Japanese (OR 3.4-4.4), while DRB1*0901-DQB1*0303 might confer a neutral or weak predisposing effect (OR 1.3-2.39) (30,32,43). In those reports, the association of haplotypes with type 1 diabetes was studied by the frequency of phenotypes, alleles, and/or haplotypes, but not by genotypic combinations, except for one study (30). In the present study, we analyzed the association by genotypic combination of haplotypes in addition to phenotypes, alleles, and haplotypes and found a differential effect of the DR4 (DRB1*0405-DQB1*0401) and DR9 (DRB1*0901-DQB1*0303) haplotypes in genotypic combination, conferring susceptibility to type 1 diabetes. Multiple logistic regression analysis of these data suggested that the DR4 haplotype predisposes in a don-Linant fashion, whereas the DR9 haplotype predisposes in a recessive fashion. These results emphasize the importance of genotypic combinations rather than alleles or haplotypes in determining the susceptibility to type 1 diabetes, and extensive analysis of genotypes, in addition to...