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Achenbach, P. ; Hummel, M.* ; Thümer, L.* ; Boerschmann, H.* ; Höfelmann, D. ; Ziegler, A.-G.

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

Diabetologia 56, 1615-1622 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.  
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Publication type Article: Journal article
Document type Scientific Article
Keywords Islet autoantibody; Progression; Susceptibility genes; Type 1 diabetes; Antibody Standardization Program ; Genome-wide Association ; T-cell Function ; Ia-2 Autoantibodies ; Risk ; Prediction ; Insulin ; Autoimmunity ; Appearance ; Diagnosis
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Journal Diabetologia
Quellenangaben Volume: 56, Issue: 7, Pages: 1615-1622 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Berlin ; Heidelberg [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research (IDF)