Association of HLA-DQ Heterodimer Residues −18β and β57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial–Type 1

• Published in: Diabetes care Vol. 45; no. 7; pp. 1610 - 1620
• Main Authors: Zhao, Lue Ping, Skyler, Jay, Papadopoulos, George K., Pugliese, Alberto, Najera, James Antonio, Bondinas, George P., Moustakas, Antonis K., Wang, Ruihan, Pyo, Chul-Woo, Nelson, Wyatt C., Geraghty, Daniel E., Lernmark, Åke
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 07.07.2022
• Subjects: Amino acids; Antibodies; Association analysis; Autoantibodies; Autoimmunity; Chains; Clinical Medicine; Clinical trials; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Disease prevention; DQA1 protein; Endocrinology and Diabetes; Endokrinologi och diabetes; Genotypes; Haplotypes; Health risks; Histocompatibility antigen HLA; Insulin; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Pathophysiology/Complications; Peptides; Protein biosynthesis; Protein synthesis; Residues
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc21-1628

The purpose was to test the hypothesis that the HLA-DQαβ heterodimer structure is related to the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D). 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 α- and β-chain amino acid residues and used in hierarchically organized haplotype (HOH) association analysis to identify motifs associated with diabetes onset. 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 -18β in the signal peptide and β57 in the β-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 (IAAs) (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 HbA1c levels throughout the follow-up. 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 be related to levels of protein synthesis and β57 to stability of the peptide-DQab trimolecular complex.