Association of HLA-DQ Heterodimer Residues-18 beta and beta 57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial-Type 1

OBJECTIVE The purpose was to test the hypothesis that the HLA-DQ alpha beta heterodimer structure is related to the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Next-generation targeted sequencing was used to genotype HLA-DQA1-B1 class II genes in 670 subjects in the Diabetes Prevention Trial-Type 1 (DPT-1). Coding sequences were translated into DQ alpha- and beta-chain amino acid residues and used in hierarchically organized haplotype (HOH) association analysis to identify motifs associated with diabetes onset. RESULTS The opposite diabetes risks were confirmed for HLA DQA1*03:01-B1*03:02 (hazard ratio [HR] 1.36; P = 2.01 * 10(-3)) and DQA1*03:03-B1*03:01 (HR 0.62; P = 0.037). The HOH analysis uncovered residue -18 beta in the signal peptide and beta 57 in the beta-chain to form six motifs. DQ*VA was associated with faster (HR 1.49; P = 6.36 * 10(-4)) and DQ*AD with slower (HR 0.64; P = 0.020) progression to diabetes onset. VA/VA, representing DQA1*03:01-B1*03:02 (DQ8/8), had a greater HR of 1.98 (P = 2.80 * 10(-3)). The DQ*VA motif was associated with both islet cell antibodies (P = 0.023) and insulin autoantibodies (IAA5) (P = 3.34 * 10(-3)), while the DQ*AD motif was associated with a decreased IAA frequency (P = 0.015). Subjects with DQ*VA and DQ*AD experienced, respectively, increasing and decreasing trends of HbA(1c) levels throughout the follow-up. CONCLUSIONS HLA-DQ structural motifs appear to modulate progression from islet autoimmunity to diabetes among at-risk relatives with islet autoantibodies. Residue -18 beta within the signal peptide may be related to levels of protein synthesis and beta 57 to stability of the peptide-DQab trimolecular complex.