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

• Published in: Diabetologia Vol. 56; no. 7; pp. 1615 - 1622
• Main Authors: Achenbach, P., Hummel, M., Thümer, L., Boerschmann, H., Höfelmann, D., Ziegler, A. G.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2013; Springer; Springer Nature B.V
• Subjects: Adaptor Proteins, Signal Transducing; Adolescent; Antigens; Autoantibodies - immunology; Biological and medical sciences; Cation Transport Proteins - immunology; Child; Child, Preschool; CTLA-4 Antigen - genetics; DEAD-box RNA Helicases - genetics; Diabetes; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic Predisposition to Disease - genetics; Genotype; HLA-DQ Antigens - genetics; Human Physiology; Humans; Infant; Infant, Newborn; Insulin; Insulin - immunology; Interferon-Induced Helicase, IFIH1; Interleukin-10 - genetics; Interleukin-18 Receptor beta Subunit - genetics; Interleukin-2 Receptor alpha Subunit - genetics; Internal Medicine; Intracellular Signaling Peptides and Proteins; Lectins, C-Type - genetics; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; 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; Germany; Progression; Islet autoantibody; Type 1 diabetes; Susceptibility genes; Endocrinopathy; Human; Autoimmunity; Immunopathology; Autoantibody; Autoimmune disease; Sensitivity; Gene; Child
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-2896-y

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.