A common non-synonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes.

Abstract

Objective: Zinc transporter 8 (SLC30A8) is a major target of autoimmunity in human type1A diabetes (T1D) and is implicated in type 2 diabetes (T2D) in genome-wide association studies. The T2D non-synonymous SNP affecting aa₃₂₅ lies within the region of highest ZnT8 autoantibody (ZnT8A) binding and prompted an investigation of its relationship to T1D.

Research Design and Methods: ZnT8A radioimmunoprecipitation assays were performed in 421 new onset T1D Caucasians using C-terminal constructs incorporating the known human aa₃₂₅ variants (Trp, Arg and Gln). Genotypes were determined by PCR-based SNP analysis.

Results: Sera from 224 subjects (53%) were reactive to Arg₃₂₅ probes, 185 (44%) to Trp₃₂₅, and 142 (34%) to Gln₃₂₅. 60 subjects reacted only with Arg₃₂₅ constructs, 31 with Trp₃₂₅ only and 1 with Gln₃₂₅ only. The restriction to either Arg₃₂₅ or Trp₃₂₅ corresponded to the inheritance of the respective C- or T alleles. A strong gene dosage effect was also evident as both Arg- and Trp restricted ZnT8A were less prevalent in heterozygotes than homozygous individuals. The SLC30A8 SNP allele frequency (75%C; 25%T) varied little with age of T1D onset or the presence of other autoantibodies.

Conclusions: The finding that diabetic autoimmunity can be defined by a single polymorphic residue has not been previously 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 since the response to ZnT8 administration could be protective or immunogenic depending on an individual's genotype.