High risk HLA-DR/DQ genotypes for IDD confer susceptibility to autoantibodies but DQB1^*0602 does not prevent them

Although HLA class II genes are important in insulin-dependent diabetes (IDD), their influence on the expression of IDD-associated autoantibodies (aAb) is unclear. We compared HLA-DRB1 and DQB1 gene frequencies in several Caucasian groups: 191 normal controls, 378 IDD patients, and 357 non-diabetic relatives of which 250 had no aAb, 107 had at least on aAb (79 ICA⁺, 31 GAD₆₅⁺ and 49 IAA⁺), and 23 had both ICA⁺ and IAA⁺. We found that the frequencies of DR3/4 or DQB1^*0201/0302 heterozygotes were significantly higher in aAb⁺ relatives compared to aAb^- relatives. The frequencies of DR4/4 or DR4/X (X=non 3 or 4) and DQB1^*0302/X (X=0201 or 0302) in aAb⁺ relatives were not different from the aAb⁻ relatives (which were enriched for these haplotypes), but were significantly higher than normal controls. The frequencies of DR3/X or DQB1^*0201/X were decreased in both aAb⁺ relatives and IDD patients. Interestingly, the dominant IDD-protective DQB1^*0602 allele allowed the development of individual aAbs (10% of ICA⁺ and 8% IAA⁺ relatives had the allele), but was not observed in any high risk double aAb⁺, or GAD₆₅Ab⁺ relatives. The latter finding was similar to that in our patients with IDD, in that only two of them (0.5%) had a DQB1^*0602 allele. In conclusion, HLA-encoded susceptibilities to disease-relevant autoantibody production and IDD are concordant with the susceptibility alleles, but discordant for the protective DQB1^*0602. Thus HLA genotyping for DQB1^*0602 would impact on the selection of aAb⁺ relatives for disease prevention trials.