Effect of the PTPN22 and INS Risk Genotypes on the Progression to Clinical Type 1 Diabetes After the Initiation of β-cell Autoimmunity
- Johanna Lempainen1,2⇓,
- Robert Hermann1,
- Riitta Veijola3,
- Olli Simell2,
- Mikael Knip4,5,6 and
- Jorma Ilonen1,7
- 1Immunogenetics Laboratory, University of Turku, Turku, Finland
- 2Department of Pediatrics, University of Turku, Turku, Finland
- 3Department of Pediatrics, University of Oulu, Oulu, Finland
- 4Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- 5Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
- 6Folkhälsan Research Center, Helsinki, Finland
- 7Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland
- Corresponding author: Johanna Lempainen, .
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.
- © 2012 by the American Diabetes Association.
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