1. Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes.
- Author
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Keiichi Kodama, Zhiyuan Zhao, Kyoko Toda, Linda Yip, Fuhlbrigge, Rebecca, Dongmei Miao, Fathman, C. Garrison, Satoru Yamada, Butte, Atul J., Liping Yu, Kodama, Keiichi, Zhao, Zhiyuan, Toda, Kyoko, Yip, Linda, Miao, Dongmei, Yamada, Satoru, and Yu, Liping
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TYPE 1 diabetes , *T cells , *ISLANDS of Langerhans , *THYMUS physiology , *LYMPH node physiology , *ANTIGENS , *ANIMAL experimentation , *AUTOIMMUNE diseases , *CARRIER proteins , *CELL culture , *COMPARATIVE studies , *GENES , *IMMUNITY , *RESEARCH methodology , *MEDICAL cooperation , *META-analysis , *MICE , *RESEARCH , *RESEARCH funding , *SEASONS , *SPLEEN , *VITAMIN D , *EVALUATION research , *CASE-control method , *SEQUENCE analysis - Abstract
Type 1 diabetes (T1D) is caused by autoreactive T cells that recognize pancreatic islet antigens and destroy insulin-producing β-cells. This attack results from a breakdown in tolerance for self-antigens, which is controlled by ectopic antigen expression in the thymus and pancreatic lymph nodes (PLNs). The autoantigens known to be involved include a set of islet proteins, such as insulin, GAD65, IA-2, and ZnT8. In an attempt to identify additional antigenic proteins, we performed an expression-based genome-wide association study using microarray data from 118 arrays of the thymus and PLNs of T1D mice. We ranked all 16,089 protein-coding genes by the likelihood of finding repeated differential expression and the degree of tissue specificity for pancreatic islets. The top autoantigen candidate was vitamin D-binding protein (VDBP). T-cell proliferation assays showed stronger T-cell reactivity to VDBP compared with control stimulations. Higher levels and frequencies of serum anti-VDBP autoantibodies (VDBP-Abs) were identified in patients with T1D (n = 331) than in healthy control subjects (n = 77). Serum vitamin D levels were negatively correlated with VDBP-Ab levels in patients in whom T1D developed during the winter. Immunohistochemical localization revealed that VDBP was specifically expressed in α-cells of pancreatic islets. We propose that VDBP could be an autoantigen in T1D. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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