title: Progression to type 1 diabetes in islet cell antibody-positive relatives in the European Nicotinamide Diabetes Intervention Trial: the role of additional immune, genetic and metabolic markers of risk.
abstract: OBJECTIVE
  To examine the role of additional immune, genetic and metabolic risk markers in determining risk of diabetes in islet cell antibody (ICA)-positive individuals with a family history of type 1 diabetes recruited into the European Nicotinamide Diabetes Intervention Trial.
  
  
  METHODS
  Five hundred and forty-nine first-degree relatives with confirmed ICA levels > or =20 Juvenile Diabetes Foundation units (mean age 15.9 years; interquartile range 10.4-33.7 years) were recruited from 20 countries. OGTTs and IVGTTs were performed at baseline, antibodies to glutamate decarboxylase (GADA), protein tyrosine phosphatase (IA-2A) and insulin (IAA) were determined by RIA, and HLA class II genotyping was performed by PCR of sequence-specific oligonucleotides.
  
  
  RESULTS
  One hundred and fifty-nine participants developed diabetes within 5 years. Univariate analysis showed that the cumulative risk of development of diabetes within 5 years varied according to age, relationship to the proband, positivity for IAA, IA-2A and GADA, number and combination of islet antibodies, HLA class II genotype, baseline glucose tolerance, and first-phase insulin secretion, but not gender or incidence of childhood type 1 diabetes in the background population. Children aged < or =10 years had a 59% risk of diabetes within 5 years, compared with 11% in those > or =25 years (p<0.0001). Using multivariate analysis, independent determinants were age, first-phase insulin response, baseline glucose tolerance and number of additional antibody markers, but not antibody type or genotype. Individuals <25 years with two or more additional antibodies at baseline had a 62% risk of diabetes within 5 years and these combined criteria identified 81% of the cases in the whole cohort.
  
  
  CONCLUSIONS
  We suggest that screening and recruitment for future intervention trials should be limited to family members aged <25 years, and should be based on islet autoantibodies alone.
authors.affiliation: Diabetes and Metabolism, Department of Clinical Science at North Bristol, University of Bristol, Southmead Hospital, UK. polly.bingley@bristol.ac.uk
authors.forename: P J
authors.initials: PJ
authors.lastname: Bingley
authors.forename: E A M
authors.initials: EA
authors.lastname: Gale
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D005060:Europe / Q000453:epidemiology; D005260:Female; D005838:Genotype; D006681:HLA-D Antigens / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D006681:HLA-D Antigens; D007328:Insulin; C024211:islet cell antibody