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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 Z...

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Autores principales: 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.
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2551679/
https://www.ncbi.nlm.nih.gov/pubmed/18591387
http://dx.doi.org/10.2337/db08-0522
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author 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.
author_facet 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.
author_sort Wenzlau, Janet M.
collection PubMed
description 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.
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spelling pubmed-25516792009-10-01 A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes 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. Diabetes Immunology and Transplantation 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. American Diabetes Association 2008-10 /pmc/articles/PMC2551679/ /pubmed/18591387 http://dx.doi.org/10.2337/db08-0522 Text en Copyright © 2008, American Diabetes Association https://creativecommons.org/licenses/by-nc-nd/3.0/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.
spellingShingle Immunology and Transplantation
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.
A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes
title A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes
title_full A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes
title_fullStr A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes
title_full_unstemmed A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes
title_short A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes
title_sort common nonsynonymous single nucleotide polymorphism in the slc30a8 gene determines znt8 autoantibody specificity in type 1 diabetes
topic Immunology and Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2551679/
https://www.ncbi.nlm.nih.gov/pubmed/18591387
http://dx.doi.org/10.2337/db08-0522
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