title: Non-HLA gene effects on the disease process of type 1 diabetes: From HLA susceptibility to overt disease.
abstract: In addition to the HLA region numerous other gene loci have shown association with type 1 diabetes. How these polymorphisms exert their function has not been comprehensively described, however. We assessed the effect of 39 single nucleotide polymorphisms (SNP) on the development of autoantibody positivity, on progression from autoantibody positivity to clinical disease and on the specificity of the antibody initiating the autoimmune process in 521 autoantibody-positive and 989 control children from a follow-up study starting from birth. Interestingly, PTPN2 rs45450798 gene polymorphism was observed to strongly affect the progression rate of beta-cell destruction after the appearance of humoral beta-cell autoimmunity. Moreover, primary autoantigen dependent associations were also observed as effect of the IKZF4-ERBB3 region on the progression rate of β-cell destruction was restricted to children with GAD antibodies as their first autoantibody whereas the effect of the INS rs 689 polymorphism was observed among subjects with insulin as the primary autoantigen. In the whole study cohort, INS rs689, PTPN22 rs2476601 and IFIH1 rs1990760 polymorphisms were associated with the appearance of beta-cell autoantibodies. These findings provide new insights into the role of genetic factors implicated in the pathogenesis of type 1 diabetes. The effect of some of the gene variants is restricted to control the initiation of β-cell autoimmunity whereas others modify the destruction rate of the β-cells. Furthermore, signs of primary autoantigen-related pathways were detected.
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland; Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland. Electronic address: johanna.lempainen@utu.fi.
authors.forename: Johanna
authors.initials: J
authors.lastname: Lempainen
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland.
authors.forename: Antti-Pekka
authors.initials: AP
authors.lastname: Laine
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Hammais
authors.affiliation: Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Department of Pediatrics, University of Turku and Turku University Hospital, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Department of Pediatrics, University of Oulu, Oulu, Finland.
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.affiliation: Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; Folkhälsan Research Center, Helsinki, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland.
authors.forename: Mikael
authors.initials: M
authors.lastname: Knip
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland; Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
mesh_terms: D000483:Alleles; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015331:Cohort Studies; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000235:genetics / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics / Q000276:immunology; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000276:immunology; D012307:Risk Factors
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D006683:HLA-DQ Antigens; D007328:Insulin; C516649:PTPN2 protein, human; C516765:PTPN22 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
keywords: Beta-cell autoimmunity; Genetics; Progression; Type 1 diabetes