title: Autoantibodies to IA-2beta improve diabetes risk assessment in high-risk relatives.
abstract: OBJECTIVE
  The aim of this study was to evaluate the prognostic significance of autoantibodies to IA-2beta (IA2betaA) in a large, well-characterised population of islet cell antibody (ICA)-positive relatives followed for 5 years in the European Nicotinamide Diabetes Intervention Trial.
  
  
  METHODS
  Autoantibodies to insulin (IAA), glutamate decarboxylase (GADA) and IA-2 (IA2A) were measured in 549 participants at study entry, and IA2A-positive samples tested for IA2betaA. First-phase insulin response (FPIR) and oral glucose tolerance were determined at baseline.
  
  
  RESULTS
  Of 212 ICA/IA2A-positive participants (median age 12.1 years; 57% male), 113 developed diabetes (5 year cumulative risk 56%), and 148 were also GADA-positive and IAA-positive (4Ab-positive). IA2betaA were detected in 137 (65%) ICA/IA2A-positive participants and were associated with an increased 5 year diabetes risk (IA2betaA-positive 65 vs 39% in IA2betaA-negative, p=0.0002). The effect was most marked in 4Ab-positive relatives (72% vs 52%, p=0.003). Metabolic testing further refined risk assessment. Among 101 4Ab-positive relatives with IA2betaA, the 5 year risk was 94% in those with a low FPIR (vs 50% in those with a normal FPIR, p<0.0001), and 95% in those with impaired glucose tolerance (IGT) (vs 66% in those with normal glucose tolerance, p<0.0001). The median time to diagnosis of 4Ab/IA2betaA-positive participants with a low FPIR was 1.5 years. Multivariate analysis confirmed IA2betaA status, antibody number, young age, FPIR and IGT as independent determinants of risk.
  
  
  CONCLUSIONS
  IA2betaA are associated with a very high risk of diabetes in ICA/IA2A-positive relatives. Testing for IA2A/IA2betaA compares favourably with the IVGTT in identifying a subgroup of autoantibody-positive relatives at increased risk. IA2betaA determination should be added to screening protocols of future intervention trials.
authors.affiliation: Diabetes Research Institute, Munich, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Achenbach
authors.forename: E
authors.initials: E
authors.lastname: Bonifacio
authors.forename: A J K
authors.initials: AJ
authors.lastname: Williams
authors.forename: A G
authors.initials: AG
authors.lastname: Ziegler
authors.forename: E A M
authors.initials: EA
authors.lastname: Gale
authors.forename: P J
authors.initials: PJ
authors.lastname: Bingley
mesh_terms: D000704:Analysis of Variance; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D003920:Diabetes Mellitus / Q000453:epidemiology* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000453:epidemiology / Q000276:immunology*; D005190:Family; D005951:Glucose Tolerance Test; D006801:Humans; D011869:Radioligand Assay; D018570:Risk Assessment
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; C096322:ICA512 autoantibody