title: The implications of autoantibodies to a single islet antigen in relatives with normal glucose tolerance: development of other autoantibodies and progression to type 1 diabetes.
abstract: OBJECTIVE
  Autoantibodies directed at single islet autoantigens are associated with lower overall risk of type 1 diabetes than multiple autoantibodies, but individuals with one autoantibody may progress to higher risk categories. We examined the characteristics of this progression in relatives followed prospectively in the TrialNet Pathway to Prevention.
  
  
  METHODS
  The study population comprised 983 relatives who were single autoantibody positive with normal baseline glucose tolerance (median age 16.2 years). Samples were screened for antibodies to GAD, insulinoma-associated antigen 2 (IA-2) and insulin, and all positive samples tested for antibodies to zinc transporter 8 and islet cell antibodies.
  
  
  RESULTS
  Antibodies to at least one additional islet autoantigen appeared in 118 of 983 relatives (overall 5 year risk 22%, 95% CI [17.9, 26.1]). At baseline, antibodies to GAD alone (68%) were more frequent than antibodies to insulin (26%) or IA-2 (6%), but all were associated with a similar risk of developing additional autoantibodies. Risk was associated with younger age (p = 0.002) and HLA class II genotype, but was similar in high and intermediate genetic risk groups (p = 0.65). Relatives who became multiple autoantibody positive during the follow-up had increased risk of developing diabetes comparable with the risk in relatives with multiple autoantibodies at study entry.
  
  
  CONCLUSIONS
  Progression of islet autoimmunity in single autoantibody positive relatives in late childhood/adult life is associated with a predominance of autoantibodies to GAD and a distinct HLA risk profile. This heterogeneity in type 1 diabetes autoimmunity has potentially important implications for disease prevention.
authors.affiliation: School of Clinical Sciences, University of Bristol, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK. polly.bingley@bristol.ac.uk.
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.affiliation: Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Boulware
authors.affiliation: Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000276:immunology*; D027682:Cation Transport Proteins / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D055815:Young Adult; D000075703:Zinc Transporter 8
chemical_list: D001323:Autoantibodies; D027682:Cation Transport Proteins; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; C024211:islet cell antibody
keywords: Autoantigens; Diabetes antibodies; GAD; HLA; IA-2; Insulin autoantibodies; Islet autoantibodies; Prediction; Prevention; Zinc transporter 8