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01.09.2009 | Article | Ausgabe 9/2009

Diabetologia 9/2009

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

Zeitschrift:
Diabetologia > Ausgabe 9/2009
Autoren:
P. Achenbach, V. Lampasona, U. Landherr, K. Koczwara, S. Krause, H. Grallert, C. Winkler, M. Pflüger, T. Illig, E. Bonifacio, A. G. Ziegler
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00125-009-1438-0) contains supplementary material, which is available to authorised users.
P. Achenbach and V. Lampasona contributed equally to this study

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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Zusatzmaterial
ESM Table 1 Distribution of SLC30A8 SNP rs13266634 genotypes in 52 ZnT8A-COOH-positive children grouped by ZnT8RA, ZnT8WA and ZnT8QA (PDF 14 kb)
125_2009_1438_MOESM1_ESM.pdf
ESM Fig. 1 ZnT8A-COOH on follow-up. Example curves are shown for children who developed both ZnT8RA and ZnT8WA (a–c) and for children with ZnT8RA but not ZnT8WA throughout follow-up (d). Circles, ZnT8RA; triangles, ZnT8WA (PDF 54 kb)
125_2009_1438_MOESM2_ESM.pdf
ESM Fig. 2 The relative strength of ZnT8RA and ZnT8WA responses over time stratified by SLC30A8 genotype in 37 children who developed ZnT8A-COOH against both aa325 variants (p = 0.004). Individual ratios of AUC for ZnT8RA divided by the AUC for ZnT8WA are plotted with respect to SLC30A8 SNP rs13266634 genotypes (CC, CT or TT) (PDF 27 kb)
125_2009_1438_MOESM3_ESM.pdf
Literatur
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