Autoantibodies Directed Toward a Novel IA-2 Variant Protein Enhance Prediction of Type 1 Diabetes
| Autor: | Liping Yu, Michael P. Morran, Dorothy J. Becker, Howard W. Davidson, Shuai Huang, Andrew D Vonberg, Massimo Pietropaolo, Charles F. Verge, Roberto Gianani, Maria Acevedo-Calado, Susan L. Pietropaolo, Stephen S. Rich, Carla J. Greenbaum, Santiago Schnell, Aaron W. Michels |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Proband Adolescent Endocrinology Diabetes and Metabolism medicine.medical_treatment 030209 endocrinology & metabolism Biology Epitope Young Adult 03 medical and health sciences 0302 clinical medicine Internal Medicine medicine Humans Receptor-Like Protein Tyrosine Phosphatases Class 8 Child Autoantibodies Genetics geography Type 1 diabetes geography.geographical_feature_category Insulin Haplotype Autoantibody Infant Middle Aged Islet medicine.disease Diabetes Mellitus Type 1 030104 developmental biology Haplotypes Child Preschool biology.protein Female Immunology and Transplantation Antibody HLA-DRB1 Chains |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | We identified autoantibodies (AAb) reacting with a variant IA-2 molecule (IA-2var) that has three amino acid substitutions (Cys27, Gly608, and Pro671) within the full-length molecule. We examined IA-2var AAb in first-degree relatives of type 1 diabetes (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 AAb 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 alters the three amino acids induces changes in the three-dimensional structure of the molecule, which may lead to epitope unmasking in the IA-2 extracellular domain. Our observations suggest that the presence of AAb 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. |
| Databáze: | OpenAIRE |
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