title: Reactivity to N-Terminally Truncated GAD65(96-585) Identifies GAD Autoantibodies That Are More Closely Associated With Diabetes Progression in Relatives of Patients With Type 1 Diabetes.
abstract: GAD autoantibodies (GADAs) identify individuals at increased risk of developing type 1 diabetes, but many people currently found to be GADA positive are unlikely to progress to clinical disease. More specific GADA assays are therefore needed. Recent international workshops have shown that the reactivity of sera from healthy donors varies according to assay type and indicated that the use of N-terminally truncated GAD65 radiolabels in GADA radiobinding assays is associated with higher specificity. To determine whether a radiobinding assay using radiolabeled GAD65(96-585) identified individuals who are at higher risk of developing diabetes, samples from recent-onset patients and GADA-positive first-degree relatives participating in the Bart's-Oxford type 1 diabetes family study were reassayed with full-length or N-terminally truncated GAD using the National Institute of Diabetes and Digestive and Kidney Diseases harmonized protocol. The sensitivity in patients was the same with both labels, but fewer relatives retested positive with truncated GAD. Among relatives who progressed to diabetes, similar proportions were found to be GADA positive when tested with either label, but because of their higher specificity the cumulative risk of diabetes was higher in those with autoantibodies to GAD65(96-585). Autoantibodies to GAD65(96-585) in relatives are more closely associated with diabetes risk than those to full-length GAD, suggesting that assays using N-terminally truncated GAD should be used to select participants for intervention trials.
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, U.K. a.j.k.williams@bristol.ac.uk.
authors.forename: Alistair J K
authors.initials: AJ
authors.lastname: Williams
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Vito
authors.initials: V
authors.lastname: Lampasona
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, U.K.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wyatt
authors.affiliation: Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Brigatti
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, U.K.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gillespie
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, U.K.
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Achenbach
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D005190:Family; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology*; D012680:Sensitivity and Specificity; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D010446:Peptide Fragments; C000602681:GAD65 (96-585); D005968:Glutamate Decarboxylase