Association of HLA-DQ Heterodimer Residues 18b and b57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial–Type 1

Abstract

OBJECTIVE The purpose was to test the hypothesis that the HLA-DQab 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 a- and b-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 5 2.01 * 1023) and DQA1*03:03-B1*03:01 (HR 0.62; P 5 0.037). The HOH analysis uncovered residue 218b in the signal peptide and b57 in the b-chain to form six motifs. DQ*VA was associated with faster (HR 1.49; P 5 6.36 * 1024) and DQ*AD with slower (HR 0.64; P 5 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 5 2.80 * 1023). The DQ*VA motif was associated with both islet cell antibodies (P 5 0.023) and insulin autoantibodies (IAAs) (P 5 3.34 * 1023), while the DQ*AD motif was associated with a decreased IAA frequency (P 5 0.015). Subjects with DQ*VA and DQ*AD experienced, respectively, increasing and decreasing trends of HbA1c 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 218b within the signal peptide may be related to levels of protein synthesis and b57 to stability of the peptide-DQab trimolecular complex.