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Association of HLA-DQ Heterodimer Residues -18ß and ß57 With Progression From Islet Autoimmunity to Diabetes in the Diabetes Prevention Trial-Type 1.
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.
Afiliación
  • Zhao LP; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Skyler J; School of Public Health, University of Washington, Seattle, WA.
  • Papadopoulos GK; Diabetes Research Institute and Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, FL.
  • Pugliese A; Laboratory of Biophysics, Biochemistry, Biomaterials and Bioprocessing, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, Arta, Greece.
  • Najera JA; Diabetes Research Institute and Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, FL.
  • Bondinas GP; School of Public Health, University of Washington, Seattle, WA.
  • Moustakas AK; Department of Food Science and Technology, Faculty of Environmental Sciences, Ionian University, Argostoli, Kefalonia, Greece.
  • Wang R; Department of Food Science and Technology, Faculty of Environmental Sciences, Ionian University, Argostoli, Kefalonia, Greece.
  • Pyo CW; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Nelson WC; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Geraghty DE; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Lernmark Å; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Diabetes Care ; 45(7): 1610-1620, 2022 07 07.
Article en En | MEDLINE | ID: mdl-35621697
OBJECTIVE: The purpose was to test the hypothesis that the HLA-DQαß 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 α- and ß-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 -18ß in the signal peptide and ß57 in the ß-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. CONCLUSIONS: HLA-DQ structural motifs appear to modulate progression from islet autoimmunity to diabetes among at-risk relatives with islet autoantibodies. Residue -18ß within the signal peptide may be related to levels of protein synthesis and ß57 to stability of the peptide-DQab trimolecular complex.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Islotes Pancreáticos / Diabetes Mellitus Tipo 1 Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Diabetes Care Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Islotes Pancreáticos / Diabetes Mellitus Tipo 1 Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: Diabetes Care Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos