Association between autoantibody markers and subtypes of DR4 and DR4-DQ in Swedish children with insulin-dependent diabetes reveals closer association of tyrosine pyrophosphatase autoimmunity with DR4 than DQ8

HLA DQA1(*)0301-DQB1(*)0302 (DQ8) and DQA1(*)0501-DQB1(*)0201 (DQ2) are positively and DQA1(*)0102-DQB1(*)0602 (DQ6) negatively associated with IDDM. In DQA1(*)0301-DQB1(*)0302 (DQ8)-positive patients, susceptibility is also mediated by DRB1(*)0401. The aim of the study was to determine the association between HLA-DR4 and DQ and the presence of GAD65, ICA512, and insulin autoantibodies as well as ICA in 425 Swedish children with IDDM and 367 controls in the age group of 0-15 years. We found that ICA512 autoantibodies were associated primarily with DRB1(*)0401 and not with DQA1(*)0301-DQB1(*)0302 (DQ8). No such hierarchy could be demonstrated for insulin autoantibodies, which were associated with both DQA1(*)0301-DQB1(*)0302 (DQ8) and DRB1(*)0401. GAD65 autoantibodies, known to be closely associated with DQA1(*)0501-DQB1(*)0201 (DQ2)-DRB1(*)0301 haplotype, also showed no preferential association with DQA1(*)0301-DQB1(*)0302 (DQ8) versus DRB1(*)04. These results suggest that the immune response to different β-cell autoantigens may be mediated via HLA class II molecules from different loci. Design of the antigen-specific immuno-intervention trials should take into account these HLA-DR and DQ subtype associations.