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Diabetes. 2019 Jun 5. pii: db181351. doi: 10.2337/db18-1351. [Epub ahead of print]

Autoantibodies Directed to a Novel IA-2 Variant Protein Enhance Prediction of Type 1 Diabetes.

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Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX.
Department of Surgery, College of Medicine, University of Toledo, OH.
Department of Molecular & Integrative Physiology, and Department of Computational Medicine and Bioinformatics, University of Michigan Ann Arbor, Michigan.
School of Women's and Children's Health, UNSW, Sydney, NSW, Australia.
Department of Pediatrics University of Pittsburgh School of Medicine.
Department of Industrial & Systems Engineering, University of Washington, Seattle, WA.
Diabetes Program, Benaroya Research Institute Seattle, WA.
Barbara Davis Center for Childhood Diabetes University of Colorado Denver, Aurora, CO.
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA.


We identified autoantibodies reacting with a variant IA-2 molecule (IA-2var) that has 3 amino acid substitutions (Cys27, Gly608 and Pro671) within the full length molecule. We examined IA-2var autoantibodies (AAb) in first-degree relatives of T1D probands from the TrialNet Pathway to Prevention Study. The presence of IA-2var-specific AAb in relatives was associated with accelerated progression to T1D in those positive for autoantibodies to GAD65 and/or insulin, but negative in the standard test for IA-2 AAb. Furthermore, relatives with single islet AAb (by traditional assays) and carrying both IA-2var AAb and the high-risk HLA-DRB1*04-DQB1*03:02 haplotype progress rapidly to onset of T1D. Molecular modeling of IA-2var predicts that the genomic variation that alter the three amino acids induce changes in the three-dimensional structure of the molecule, that may lead to epitope unmasking in the IA-2 extracellular domain.Our observations suggest that the presence of autoantibodies to IA-2var would identify high risk subjects who would benefit from participation in prevention trials who have one islet antibody by traditional testing, and otherwise would be misclassified as "low risk" relatives.


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