Details

Autor(en) / Beteiligte

• Wenzlau, Janet M
• Liu, Yu
• Yu, Liping
• Moua, Ong
• Fowler, Kimberly T
• Rangasamy, Sampathkumar
• Walters, Jay
• Eisenbarth, George S
• Davidson, Howard W
• Hutton, John C

Titel

A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes

Ist Teil von

• Diabetes (New York, N.Y.), 2008-10, Vol.57 (10), p.2693-2697

Ort / Verlag

United States: American Diabetes Association

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes Janet M. Wenzlau 1 , Yu Liu 2 , Liping Yu 1 , Ong Moua 1 , Kimberly T. Fowler 1 , Sampathkumar Rangasamy 1 , Jay Walters 1 , George S. Eisenbarth 1 , Howard W. Davidson 1 and John C. Hutton 1 1 Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado 2 Department of Endocrinology, Nanjing Medical University, First Affiliated Hospital, Nanjing, China Corresponding author: John C. Hutton, john.hutton{at}uchsc.edu Abstract 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. 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 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. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 30 June 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 24, 2008. Received February 2, 2008. DIABETES