Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes

Diabetes. 2016 May;65(5):1341-9. doi: 10.2337/db15-1308. Epub 2016 Mar 16.

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.

Publication types

  • Meta-Analysis

MeSH terms

  • Adolescent
  • Animals
  • Autoantigens / genetics
  • Autoantigens / metabolism*
  • Autoimmune Diseases / blood
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism*
  • Autoimmune Diseases / pathology
  • Autoimmunity*
  • Case-Control Studies
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Colorado
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Female
  • Gene Expression Regulation, Developmental*
  • Genome-Wide Association Study
  • Glucagon-Secreting Cells / immunology
  • Glucagon-Secreting Cells / metabolism*
  • Glucagon-Secreting Cells / pathology
  • Humans
  • Male
  • Mice, Inbred NOD
  • Organ Specificity
  • Seasons
  • Spleen / cytology
  • Spleen / immunology
  • Spleen / metabolism
  • Spleen / pathology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Vitamin D / analogs & derivatives
  • Vitamin D / blood
  • Vitamin D-Binding Protein / genetics
  • Vitamin D-Binding Protein / metabolism*

Substances

  • Autoantigens
  • Vitamin D-Binding Protein
  • Vitamin D
  • 25-hydroxyvitamin D