期刊
DIABETES
卷 57, 期 10, 页码 2693-2697出版社
AMER DIABETES ASSOC
DOI: 10.2337/db08-0522
关键词
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资金
- the Childhood Diabetes Foundation in Denver
- the University of Colorado Health Sciences Diabetes and Endocrinology Research Center [P30 DK57516]
- NIH [R01 DK052068]
- Juvenile Diabetes Research Foundation Center
- American Diabetes Association (ADA)
OBJECTIVE-Zinc transporter eight (SLC30A8) is a major target of autoimmunity in human type IA 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. RESEARCH DESIGN AND METHODS-ZnT8A radioimmuno-precipitation 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.
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