title: Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes.
abstract: Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes-affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs), tissue transglutaminase, and 21-hydroxylase was tested using a linear mixed-model regression approach to simultaneously control for population structure and family relatedness. Four loci were associated with autoantibody positivity at genome-wide significance. Positivity for GADA was associated with 3q28/LPP, for IA-2A with 1q23/FCRL3 and 11q13/RELA, and for PCAs with 2q24/IFIH1. The 3q28 locus showed association after only 3 years duration and might therefore be a marker of persistent GADA positivity. The 1q23, 11q13, and 2q24 loci were associated with autoantibodies close to diabetes onset and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity.
authors.affiliation: Department of Pediatrics, Herlev University Hospital, Herlev, Denmark.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Brorsson
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Virginia, Charlottesville, VA Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Janet
authors.initials: J
authors.lastname: Wenzlau
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: Peter
authors.initials: P
authors.lastname: Baker
authors.affiliation: Diabetes & Metabolism, School of Clinical Sciences, University of Bristol, Bristol, U.K.
authors.forename: Alistair J K
authors.initials: AJ
authors.lastname: Williams
authors.affiliation: Diabetes & Metabolism, School of Clinical Sciences, University of Bristol, Bristol, U.K.
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: John C
authors.initials: JC
authors.lastname: Hutton
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
authors.forename: George S
authors.initials: GS
authors.lastname: Eisenbarth
authors.affiliation: Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA Department of Public Health Sciences, Division of Biostatistics and Epidemiology, University of Virginia, Charlottesville, VA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Department of Pediatrics, Herlev University Hospital, Herlev, Denmark flemming.pociot.01@regionh.dk.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans
chemical_list: D001323:Autoantibodies
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