Effect of the PTPN22 and INS Risk Genotypes on the Progression to Clinical Type 1 Diabetes After the Initiation of β-Cell Autoimmunity

  1. Jorma Ilonen1,7
  1. 1Immunogenetics Laboratory, University of Turku, Turku, Finland
  2. 2Department of Pediatrics, University of Turku, Turku, Finland
  3. 3Department of Pediatrics, University of Oulu, Oulu, Finland
  4. 4Department of Pediatrics, Tampere University Hospital, Tampere, Finland
  5. 5Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
  6. 6Folkhälsan Research Center, Helsinki, Finland
  7. 7Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland
  1. Corresponding author: Johanna Lempainen, johanna.lempainen{at}utu.fi.

Abstract

We set out to analyze the role of two major non-HLA gene polymorphisms associated with type 1 diabetes (T1D), PTPN22 1858C/T and insulin gene INS−23 A/T in progression to clinical T1D after the appearance of β-cell autoimmunity. The study population comprised 249 children with HLA-associated T1D susceptibility. All subjects were persistently positive for at least one of the T1D-associated biochemically defined autoantibodies (insulin autoantibody, GAD antibody, or IA-2 antibody), and 136 subjects presented with T1D over a median follow-up of 4.3 years (range 0.0–12.5) after the appearance of the first autoantibody. The PTPN22 1858T allele was strongly associated with progression to T1D after the appearance of the first biochemically defined β-cell autoantibody (hazard ratio 1.68 [95% CI 1.09–2.60], P = 0.02 Cox regression analysis, multivariate test), and the effect remained similar when analyzed after the appearance of the second autoantibody (P = 0.013), whereas INS−23 HphI AA genotype was not associated with progression to clinical diabetes after the appearance of the first or second autoantibody (P = 0.38 and P = 0.88, respectively). The effect of the INS risk genotype seems to be limited to the induction and early phases of β-cell autoimmunity, but the PTPN22 1858T allele instead affects the initiation and late progression phase of diabetes-associated autoimmunity.

  • Received March 22, 2011.
  • Accepted January 23, 2012.

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  1. Diabetes vol. 61 no. 4 963-966
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