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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.

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posted on 27.05.2022, 13:51 authored by Lue Ping Zhao, Jay Skyler, George K. Papadopoulos, Alberto Pugliese, James Antonio Najera, George P. Bondinas, Antonis K. Moustakas, Ruihan Wang, Chul-Woo Pyo, Wyatt C. Nelson, Daniel E. Geraghty, Åke Lernmark
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.

Funding

The study was supported by a grant (1R56 DK117276) from National Institute of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The molecular simulation studies by AKM, GBP and GKP reported here were supported by grants from the Technological Educational Institute of Epirus Research Committee, a Biotech4 grant from the European Union (contract no. BIO4 CT95 0263), a supplementary grant from the Hellenic Secretariat of Research and Technology, and a grant from the European Union’s Third EU Regional Development Framework for Greece (EPEAEK II scheme, Program “Archimedes).

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