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Achenbach, P. ; Lampasona, V.* ; Landherr, U. ; Koczwara, K. ; Krause, S.* ; Grallert, H. ; Winkler, C. ; Pflüger, M. ; Illig, T. ; Bonifacio, E.* ; Ziegler, A.-G.

Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk.

Diabetologia 52, 1881-1888 (2009)
Publ. Version/Full Text DOI
Our aim was to determine the relationships between autoantibodies to zinc transporter 8 (ZnT8), genotypes of the ZnT8-encoding gene SLC30A8 and type 1 diabetes risk. ZnT8 autoantibodies (ZnT8A) were measured in sera of 1,633 children with a first-degree family history of type 1 diabetes and who were prospectively followed from birth. Antibodies were measured by Protein A-based radiobinding assays and COOH-terminal (R325, W325 or Q325 variants) or NH2-terminal constructs of human ZnT8. SLC30A8 genotyping at single-nucleotide polymorphism (SNP) rs13266634 was performed on 1,170 children. Antibodies against COOH-terminal ZnT8 constructs (ZnT8A-COOH) developed in 58 children as early as 9 months of age (median 3 years). They were detected in 55 of 128 (43%) children with autoantibodies to insulin, GAD and/or insulinoma-associated protein 2 and 34 of 42 (81%) who progressed to diabetes. The additional presence of ZnT8A-COOH stratified diabetes risk in islet autoantibody-positive children (p < 0.0001). SLC30A8 genotype strongly influenced ZnT8A type and diabetes risk in ZnT8A-COOH-positive children. Antibody binding against the ZnT8 R325 variant was strictly correlated with the number of the corresponding SLC30A8 R325-encoding alleles, whereas binding against the W325 variant was highest in children who had SLC30A8 W325-encoding alleles (p = 0.001). Moreover, ZnT8A-COOH-positive children who carried homozygous SLC30A8 SNP rs13266634 genotypes progressed faster to diabetes than those who were heterozygous (59% [95% CI 42.3-75.7%] vs 22% [95% CI 0-44.3%] within 5 years; p = 0.01). Autoimmunity against the COOH-terminal region of ZnT8 is a highly relevant prognostic feature in childhood type 1 diabetes. Risk stratification in ZnT8A-COOH-positive children is further improved by SLC30A8 genotyping.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Autoantibody; Prediction; SLC30A8; Type 1 diabetes; Zinc transporter; ZnT8; genome-wide association; antibody-positive relatives; autoimmunity; progression; immune; loci; susceptibility; identification; decarboxylase; specificity
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Journal Diabetologia
Quellenangaben Volume: 52, Issue: 9, Pages: 1881-1888 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Berlin ; Heidelberg [u.a.]
Reviewing status
Institute(s) Institute of Diabetes Research Type 1 (IDF)
Institute of Epidemiology I (EPI1)
Institute for Pancreatic Beta Cell Research (IPI)