title: Expression-Based Genome-Wide Association Study Links Vitamin D-Binding Protein With Autoantigenicity in Type 1 Diabetes.
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.
authors.affiliation: Institute for Computational Health Sciences, Department of Pediatrics, University of California, San Francisco, San Francisco, CA keiichi.kodama@ucsf.edu.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kodama
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Biomedical Research Center, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Toda
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: Linda
authors.initials: L
authors.lastname: Yip
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fuhlbrigge
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Miao
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA.
authors.forename: C Garrison
authors.initials: CG
authors.lastname: Fathman
authors.affiliation: Diabetes Center, Kitasato Institute Hospital, Kitasato University, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Institute for Computational Health Sciences, Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO liping.yu@ucdenver.edu.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015551:Autoimmunity; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003120:Colorado; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055106:Genome-Wide Association Study; D050416:Glucagon-Secreting Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D009928:Organ Specificity; D012621:Seasons; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D014809:Vitamin D-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D001324:Autoantigens; D014809:Vitamin D-Binding Protein; D014807:Vitamin D; C104450:25-hydroxyvitamin D