A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes.
OBJECTIVE
Zinc transporter eight (SLC30A8) is a major target of autoimmunity in human type 1A diabetes and is implicated in type 2 diabetes in genome-wide association studies. The type 2 diabetes nonsynonymous single nucleotide polymorphism (SNP) affecting aa(325) lies within the region of highest ZnT8 autoantibody (ZnT8A) binding, prompting an investigation of its relationship to type 1 diabetes.


METHODS
ZnT8A radioimmunoprecipitation assays were performed in 421 new-onset type 1 diabetic Caucasians using COOH-terminal constructs incorporating the known human aa(325) variants (Trp, Arg, and Gln). Genotypes were determined by PCR-based SNP analysis. RESULTS-Sera from 224 subjects (53%) were reactive to Arg(325) probes, from 185 (44%) to Trp(325)probes, and from 142 (34%) to Gln(325)probes. Sixty subjects reacted only with Arg(325) constructs, 31 with Trp(325) only, and 1 with Gln(325) only. The restriction to either Arg(325) or Trp(325) corresponded with inheritance of the respective C- or T-alleles. A strong gene dosage effect was also evident because both Arg- and Trp-restricted ZnT8As were less prevalent in heterozygous than homozygous individuals. The SLC30A8 SNP allele frequency (75% C and 25% T) varied little with age of type 1 diabetes onset or the presence of other autoantibodies.


CONCLUSIONS
The finding that diabetes autoimmunity can be defined by a single polymorphic residue has not previously been documented. It argues against ZnT8 autoimmunity arising from molecular mimicry and suggests a mechanistic link between the two major forms of diabetes. It has implications for antigen-based therapeutic interventions because the response to ZnT8 administration could be protective or immunogenic depending on an individual's genotype.
Wenzlau
Janet M
JM
Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, USA.
Liu
Yu
Y
Yu
Liping
L
Moua
Ong
O
Fowler
Kimberly T
KT
Rangasamy
Sampathkumar
S
Walters
Jay
J
Eisenbarth
George S
GS
Davidson
Howard W
HW
Hutton
John C
JC
D000293:Adolescent; D000328:Adult; D000918:Antibody Specificity / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D027682:Cation Transport Proteins / Q000235:genetics* / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D005838:Genotype; D006801:Humans; D007223:Infant; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult; D000075703:Zinc Transporter 8
D001323:Autoantibodies; D027682:Cation Transport Proteins; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8