A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes.
A common nonsynonymous single nucleotide polymorphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes.
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作者：
Wenzlau JM;Liu Y;Yu L;Moua O;Fowler KT;Rangasamy S;Walters J;Eisenbarth GS;Davidson HW;Hutton JC
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 aa325 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 radioimmunoprecipitation assays were performed in 421 new-onset type 1 diabetic Caucasians using COOH-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, from 185 (44%) to Trp325probes, and from 142 (34%) to Gln325probes. Sixty subjects reacted only with Arg325 constructs, 31 with Trp325 only, and 1 with Gln325 only. The restriction to either Arg325 or Trp325 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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DOI：
10.1097/med.0b013e32825a673b
发表时间：
2007-08-01
期刊：
Current opinion in endocrinology, diabetes, and obesity
影响因子：
--
作者：
Haller, Michael J;Gottlieb, Peter A;Schatz, Desmond A
通讯作者：
Schatz, Desmond A
DOI：
10.1073/pnas.0705894104
发表时间：
2007-10-23
影响因子：
11.1
作者：
Wenzlau, Janet M.;Juhl, Kirstine;Hutton, John C.
通讯作者：
Hutton, John C.
影响因子：
8.2
作者：
Boesgaard, T. W.;Zilinskaite, J.;Hansen, T.
通讯作者：
Hansen, T.
影响因子：
1.2
作者：
Osame, Keiichiro;Takahashi, Yoshihiko;Noda, Mitsuhiko
通讯作者：
Noda, Mitsuhiko
影响因子：
46.9
作者：
Honeyman, MC;Brusic, V;Harrison, LC
通讯作者：
Harrison, LC