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- Title:
Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk.
- Document type:
- Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Article
- Author(s):
- Achenbach, P; Lampasona, V; Landherr, U; Koczwara, K; Krause, S; Grallert, H; Winkler, C; Pflüger, M; Illig, T; Bonifacio, E; Ziegler, AG
- 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 NH(2)-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.
- Journal title abbreviation:
- Diabetologia
- Year:
- 2009
- Journal volume:
- 52
- Journal issue:
- 9
- Pages contribution:
- 1881-8
- Language:
- eng
- Fulltext / DOI:
- doi:10.1007/s00125-009-1438-0
- Pubmed ID:
- http://view.ncbi.nlm.nih.gov/pubmed/19590848
- Print-ISSN:
- 0012-186X
- TUM Institution:
- Klinik und Poliklinik für Kinderheilkunde und Jugendmedizin
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