Transracial evidence for the influence of the homologous HLA DR-DQ haplotype on transmission of HLA DR4 haplotypes to diabetic children

The HLA-DQB1*0302 allele on DR4 haplotypes is a marker for type 1 diabetes susceptibility and it is an especially high-risk allele in DR3/4 because of its preferential distribution in Caucasian DR3/4 patients. In Asians, not only DQB1*0302 but also DQB1*0401 on DR4 haplotypes are associated with typ e 1 diabetes. We investigated whether the contribution of these DQ molecule s was also genotype-dependent in Asians. Although the prevalence of the DR4 -DQB1*0302 haplotype did nor differ in patients vs. controls, the DR3/4-DQB 1*0302 genotype had a RR of 12 (P<10(-4)). Moreover, a significant associat ion of DQB1*0302 with the DR3/4 genotype was found (RR=3, P<10(-2)). In con trast, the distribution of DQB1*0401 alleles of DR4/X (X: other than 3, 4) is different from that of DR3/4 and DR4/4. Especially a significant associa tion of DQB1*0401 with DR4/X (X: other than 1, 3, 4) was found (RR=3, P<10( -3)). The frequency of transmission of the DR4-DQB1*0302 haplotypes to diab etic offspring with DR3 was 80%, while to those without DR3 was 40%. In con trast, the transmission of the DR4-DQB1*0401 to those with DR3 was 60%, whi le to those without DR3 was 80%. High-risk DR4 subtypes were predominant in DR4/X (RR=7, P<10(-3)), whereas protective DR4 subtypes were observed main ly in the DR3/4 (RR=3, P<0.05). The association with diabetes and transmiss ion to a diabetic offspring of DR4 haplotypes varies depending on the haplo type borne on the homologous chromosome. This might contribute not only to the synergistic effect of DR3/4, but also to the susceptibility influence o f HLA DQBl*0401 alleles confined to DR4/X.