HLA-DQA1 and DQB1 Alleles associated with genetic susceptibility to IDDM in a black population

Transracial analysis provides a method of distinguishing primary associations between insulin-dependent diabetes mellitus (IDDM) and HLA class II alleles from those secondary to linkage disequilibrium. Blacks show DR-DQ relationships that are different from other races and are a useful group in which to investigate HLA-D region associations with IDDM. In this study, the frequencies of HLA-DQA1 and -DQB1 alleles in Afro-Caribbean IDDM and control subjects were compared. Alleles were identified with sequence-specific oligonucleotide probing. The DQA1 allele A3 was positively associated with IDDM (relative risk[RR] = 25.3, corrected P [Pc]<7.0 x 10 -6). THe DQB1 alleles DQw2 and DQw8 were also positively associated (RR = 4.7, Pc<6.5 x 10 -3 and RR = 12.3,Pc = 3.4 x 10 -3, respectively). The A1.2 and DQw6 alleles were negatively associated (RR = 0.16, Pc<3.5 x 10 -3 and RR = 0.15, Pc = 2.4 x 10 -2, respectively). These findings were compared to data from other races. The positive associations with A3 and DQw2 are consistent with all racial groups investigated. The negative association with DQw6 is present in all racial groups in which it is a common allele. These findings suggest that DQ alleles, and hence DQ molecules, may directly affect predisposition to IDDM. (AU)

Trans-racial studies implicate HLA-DQ as a component of genetic susceptibility to Type 1 (insulin-dependent) diabetes

Type 1 (insulin-dependent) diabetic patients and control subjects of Afro-Caribbean Negroid racial origin were investigated by serological HLA-DR-typing and restriction fragment length polymorphism analysis using DNA probes corresponding to the DQO, DQá and DRá chain genes. Combined analysis indicated that four DR antigens are positively associated with the condition in Negroid subjects - DR3, 4, 7 and w9. DR3 and 4 are also associated in Caucasians, but the relative risk for DR3 is lower in Negroid subjects. The DR7 association is specific for the Negroid race, and DRw9 is only weakly associated in Caucasoid subjects. Restriction fragment length polymorphism analysis demonstrated a DQá restriction pattern in Negroid subjects which is absent from Caucasoid subjects. This pattern was associated with DRw9 and a subset of DR7, and was markedly increased in frequency in diabetic patients compared with control subjects (48.7 percent vs 10.4 percent respectively; p<10 -4). In the absence of this pattern, DR7 showed no positive association. DR3 in Negroid subjects was associated with two distinct DQO-DQá patterns, only one of which was positively associated with diabetes. A DQá pattern, in linkage disequilibrium with different DR antigens in different races, conferred a consistent protective effect against the development of Type 1 diabetes. Trans-racial genetic analysis thus supports a primary role for DQ in susceptibility to Type 1 diabetes. (AU)