title: Combination of autoantibody markers and risk for development of type 1 diabetes: results from a large french cohort of family members.
abstract: BACKGROUND
  The aims of the study were to characterize the relatives at high risk of progression to diabetes and to determine whether rate of progression to diabetes varied according to age, specific combination of antibodies and genetic markers of susceptibility.
  
  
  METHODS
  Family members of type 1 diabetic patients were examined through a large medical network for the presence of specific antibodies to beta cell constituents and high risk DQB1 alleles. Antibodies to insulin, GAD and IA-2 as well as ICA were examined in 4,044 family members recruited in a large prospective family study in the Rhone-Alpes region (the GRADI study). Among them, 3,951 non diabetic first degree relatives have been tested on a median of 2.2 occasions and were followed for up to 16 years.
  
  
  RESULTS
  Presence of antibodies to GAD (3.6%), IA-2 (4.9%), insulin (2.2%) and ICA at titers equal or above 20JDF units (1.1%) were noticed at the first determination and prevalence increased among ICA positive relatives versus ICA negative relatives. All combinations of markers resulted in specificities above 90%. The positive predictive value of antibodies was dependent on the number of positive antibodies. Combination of antibodies to GAD and IA-2 or GAD and IAA had higher predictive values and sensitivities than ICA titers above 20 JDF units. Additional positivity of IAA increased the predictive value but reduced the sensitivity of the screening procedure. Using a combi GAD/IA-2 assay increased the sensitivity of the screening up to 87.8% but reduced the predictive value to 13.8%.
  
  
  CONCLUSIONS
  These data confirm in a large French cohort of first degree relatives of type 1 diabetic patients that combinations of antibodies to beta cell constituents can replace ICA in the first screening procedure. We report that combi GAD/IA-2 assay is well suited for screening purposes. However, time to diabetes in antibody positive relatives appears to be more heterogeneous to what has been described. The importance of genetic markers needs further evaluation.
authors.affiliation: Department of Endocrinology, Hopital Edouard Herriot and INSERM 449, Lyon, France. charles.thivolt@chu-lyon.fr
authors.forename: C
authors.initials: C
authors.lastname: Thivolet
authors.forename: M
authors.initials: M
authors.lastname: Nicolino
authors.forename: S
authors.initials: S
authors.lastname: Monbeig
authors.forename: B
authors.initials: B
authors.lastname: Estour
authors.forename: S
authors.initials: S
authors.lastname: Halimi
authors.forename: M
authors.initials: M
authors.lastname: Robert
authors.forename: J
authors.initials: J
authors.lastname: Orgiazzi
authors.forename: P
authors.initials: P
authors.lastname: Chatelain
mesh_terms: D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000453:epidemiology / Q000276:immunology*; D005190:Family; D005260:Female; D005500:Follow-Up Studies; D005602:France / Q000453:epidemiology; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology; D008297:Male; D011237:Predictive Value of Tests; D012306:Risk; D012307:Risk Factors; D035781:Siblings; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; C096322:ICA512 autoantibody