Two residues (-18β and β57) in the HLA-DQ heterodimer were critically associated with progression from islet autoimmunity to diabetes in the DPT-1 trial.

Objective The purpose was to test the hypothesis that HLA DQab heterodimer structure was 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-1 (DPT-1) study. Coding sequences were translanted 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 (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 -18β in the signal peptide and β57 in the b 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), subjects had greater hazard ratio (HR = 1.98, p = 2.80*10^-3). The DQ*VA motif was associated with both islet cell antibodies (ICA) (p = 0.023) and insulin autoantibodies (IAA)(p = 3.34*10^-3 ), while the DQ*AD motif was associated with a decreased IAA frequency (p = 0.015). DQ*VA and DQ*AD subjects 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 -18β within the signal peptide may relate to levels of protein synthesis and β57 to stability of the DQ trimolecular complex.