Characteristics of rapid vs slow progression to type 1 diabetes in multiple islet autoantibody-positive children

Diabetologia. 2013 Jul;56(7):1615-22. doi: 10.1007/s00125-013-2896-y. Epub 2013 Mar 29.


Aims/hypothesis: 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/interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adolescent
  • Autoantibodies / immunology*
  • CTLA-4 Antigen / genetics
  • Cation Transport Proteins / immunology*
  • Child
  • Child, Preschool
  • DEAD-box RNA Helicases / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 1 / pathology*
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • HLA-DQ Antigens / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Insulin / immunology*
  • Interferon-Induced Helicase, IFIH1
  • Interleukin-10 / genetics
  • Interleukin-18 Receptor beta Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Intracellular Signaling Peptides and Proteins
  • Lectins, C-Type / genetics
  • Male
  • Microfilament Proteins / genetics
  • Monosaccharide Transport Proteins / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics
  • Proteins / genetics
  • Receptor, ErbB-3 / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / immunology*
  • Zinc Transporter 8


  • Adaptor Proteins, Signal Transducing
  • Autoantibodies
  • CLEC16A protein, human
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Cation Transport Proteins
  • Cobl protein, human
  • HLA-DQ Antigens
  • IL18RAP protein, human
  • Insulin
  • Interleukin-18 Receptor beta Subunit
  • Interleukin-2 Receptor alpha Subunit
  • Intracellular Signaling Peptides and Proteins
  • Lectins, C-Type
  • Microfilament Proteins
  • Monosaccharide Transport Proteins
  • Proteins
  • SH2B3 protein, human
  • SLC30A8 protein, human
  • Zinc Transporter 8
  • Interleukin-10
  • ERBB3 protein, human
  • Receptor, ErbB-3
  • PTPN2 protein, human
  • PTPN22 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8
  • IFIH1 protein, human
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1