title: Characteristics of rapid vs slow progression to type 1 diabetes in multiple islet autoantibody-positive children.
abstract: OBJECTIVE
  Islet autoantibody-positive children progress to type 1 diabetes at variable rates. In our study, we asked whether characteristic autoantibody and/or gene profiles could be defined for phenotypes showing extreme progression.
  
  
  METHODS
  Autoantibodies to insulin (IAA), GAD (GADA), insulinoma-associated antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A) were measured in follow-up sera, and genotyping for type 1 diabetes susceptibility genes (HLA-DR/HLA-DQ, INS variable number of tandem repeats [VNTR] and single nucleotide polymorphisms at PTPN22, PTPN2, ERBB3, IL2, SH2B3, CTLA4, IFIH1, KIAA0350 [also known as CLEC16A], CD25, IL18RAP, IL10, COBL) was performed on the DNA samples of children born to a parent with type 1 diabetes and prospectively followed from birth for up to 22 years.
  
  
  RESULTS
  Of the 1,650 children followed, 23 developed multiple autoantibodies and progressed to diabetes within 3 years (rapid progressors), while 24 children developed multiple autoantibodies and remained non-diabetic for more than 10 years from seroconversion (slow progressors). Rapid and slow progressors were similar with respect to HLA-DR/HLA-DQ genotypes, development of IAA, GADA and ZnT8A, and progression to multiple autoantibodies. In contrast, IA-2A development was considerably delayed in the slow progressors. Furthermore, both groups were effectively distinguished by the combined presence or absence of type 1 diabetes susceptibility alleles of non-HLA genes, most notably IL2, CD25, INS VNTR, IL18RAP, IL10, IFIH1 and PTPN22, and discrimination was improved among children carrying high-risk HLA-DR/HLA-DQ genotypes.
  
  
  CONCLUSIONS
  Our data suggest that genotypes of non-HLA type 1 diabetes susceptibility genes influence the likelihood or rate of diabetes progression among children with multiple islet autoantibodies.
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, Ingolstaedter Landstrasse 1, 85764, Neuherberg, Germany. peter.achenbach@helmholtz-muenchen.de
authors.forename: P
authors.initials: P
authors.lastname: Achenbach
authors.forename: M
authors.initials: M
authors.lastname: Hummel
authors.forename: L
authors.initials: L
authors.lastname: Thümer
authors.forename: H
authors.initials: H
authors.lastname: Boerschmann
authors.forename: D
authors.initials: D
authors.lastname: Höfelmann
authors.forename: A G
authors.initials: AG
authors.lastname: Ziegler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000235:genetics; D027682:Cation Transport Proteins / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D053487:DEAD-box RNA Helicases / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000276:immunology*; D000072640:Interferon-Induced Helicase, IFIH1; D016753:Interleukin-10 / Q000235:genetics; D053728:Interleukin-18 Receptor beta Subunit / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type / Q000235:genetics; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000235:genetics; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics; D011506:Proteins / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000235:genetics; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology*; D000075703:Zinc Transporter 8
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001323:Autoantibodies; C522505:CLEC16A protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D027682:Cation Transport Proteins; C561633:Cobl protein, human; D006683:HLA-DQ Antigens; C115629:IL18RAP protein, human; D007328:Insulin; D053728:Interleukin-18 Receptor beta Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008840:Microfilament Proteins; D009004:Monosaccharide Transport Proteins; D011506:Proteins; C490778:SH2B3 protein, human; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D016753:Interleukin-10; C581292:ERBB3 protein, human; D020893:Receptor, ErbB-3; C516649:PTPN2 protein, human; C516765:PTPN22 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
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