title: Effect of the PTPN22 and INS risk genotypes on the progression to clinical type 1 diabetes after the initiation of β-cell autoimmunity.
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.
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland. johanna.lempainen@utu.fi
authors.forename: Johanna
authors.initials: J
authors.lastname: Lempainen
authors.forename: Robert
authors.initials: R
authors.lastname: Hermann
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
mesh_terms: D015551:Autoimmunity; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000378:metabolism; D008297:Male; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012307:Risk Factors
chemical_list: D007328:Insulin; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22