Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk.
OBJECTIVE
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
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.
Achenbach
P
P
Diabetes Research Institute of Forschergruppe Diabetes e.V., Helmholtz Center Munich, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany.
Lampasona
V
V
Landherr
U
U
Koczwara
K
K
Krause
S
S
Grallert
H
H
Winkler
C
C
Pflüger
M
M
Illig
T
T
Bonifacio
E
E
Ziegler
A G
AG
D000293:Adolescent; D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics*; D005500:Follow-Up Studies; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007330:Insulin Antibodies / Q000097:blood / Q000235:genetics / Q000276:immunology; D015993:Life Tables; D000075703:Zinc Transporter 8
D001323:Autoantibodies; D027682:Cation Transport Proteins; D007330:Insulin Antibodies; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8