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Erschienen in: Diabetologia 9/2009

01.09.2009 | Article

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

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

Erschienen in: Diabetologia | Ausgabe 9/2009

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Abstract

Aims/hypothesis

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.

Methods

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.

Results

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).

Conclusions/interpretation

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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Metadaten
Titel
Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk
verfasst von
P. Achenbach
V. Lampasona
U. Landherr
K. Koczwara
S. Krause
H. Grallert
C. Winkler
M. Pflüger
T. Illig
E. Bonifacio
A. G. Ziegler
Publikationsdatum
01.09.2009
Verlag
Springer-Verlag
Erschienen in
Diabetologia / Ausgabe 9/2009
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-009-1438-0

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