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Role of Type 1 Diabetes–Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study

The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children de...

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Autores principales: Törn, Carina, Hadley, David, Lee, Hye-Seung, Hagopian, William, Lernmark, Åke, Simell, Olli, Rewers, Marian, Ziegler, Anette, Schatz, Desmond, Akolkar, Beena, Onengut-Gumuscu, Suna, Chen, Wei-Min, Toppari, Jorma, Mykkänen, Juha, Ilonen, Jorma, Rich, Stephen S., She, Jin-Xiong, Steck, Andrea K., Krischer, Jeffrey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407865/
https://www.ncbi.nlm.nih.gov/pubmed/25422107
http://dx.doi.org/10.2337/db14-1497
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author Törn, Carina
Hadley, David
Lee, Hye-Seung
Hagopian, William
Lernmark, Åke
Simell, Olli
Rewers, Marian
Ziegler, Anette
Schatz, Desmond
Akolkar, Beena
Onengut-Gumuscu, Suna
Chen, Wei-Min
Toppari, Jorma
Mykkänen, Juha
Ilonen, Jorma
Rich, Stephen S.
She, Jin-Xiong
Steck, Andrea K.
Krischer, Jeffrey
author_facet Törn, Carina
Hadley, David
Lee, Hye-Seung
Hagopian, William
Lernmark, Åke
Simell, Olli
Rewers, Marian
Ziegler, Anette
Schatz, Desmond
Akolkar, Beena
Onengut-Gumuscu, Suna
Chen, Wei-Min
Toppari, Jorma
Mykkänen, Juha
Ilonen, Jorma
Rich, Stephen S.
She, Jin-Xiong
Steck, Andrea K.
Krischer, Jeffrey
author_sort Törn, Carina
collection PubMed
description The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GAD antibody, IA-2A, or micro insulin autoantibodies) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with T1D in the genome-wide association scan meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY participants carrying high-risk HLA genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (P < 0.05), whereof four were significant after adjustment for multiple testing (P < 0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27–1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14–1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19–1.61]), and rs1004446 in INS (HR 0.77 [0.66–0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70–3.44]). Although genes in the HLA region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease.
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spelling pubmed-44078652016-05-01 Role of Type 1 Diabetes–Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study Törn, Carina Hadley, David Lee, Hye-Seung Hagopian, William Lernmark, Åke Simell, Olli Rewers, Marian Ziegler, Anette Schatz, Desmond Akolkar, Beena Onengut-Gumuscu, Suna Chen, Wei-Min Toppari, Jorma Mykkänen, Juha Ilonen, Jorma Rich, Stephen S. She, Jin-Xiong Steck, Andrea K. Krischer, Jeffrey Diabetes Genetics/Genomes/Proteomics/Metabolomics The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GAD antibody, IA-2A, or micro insulin autoantibodies) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with T1D in the genome-wide association scan meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY participants carrying high-risk HLA genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (P < 0.05), whereof four were significant after adjustment for multiple testing (P < 0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27–1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14–1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19–1.61]), and rs1004446 in INS (HR 0.77 [0.66–0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70–3.44]). Although genes in the HLA region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease. American Diabetes Association 2015-05 2014-11-24 /pmc/articles/PMC4407865/ /pubmed/25422107 http://dx.doi.org/10.2337/db14-1497 Text en © 2015 by the American Diabetes Association. 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.
spellingShingle Genetics/Genomes/Proteomics/Metabolomics
Törn, Carina
Hadley, David
Lee, Hye-Seung
Hagopian, William
Lernmark, Åke
Simell, Olli
Rewers, Marian
Ziegler, Anette
Schatz, Desmond
Akolkar, Beena
Onengut-Gumuscu, Suna
Chen, Wei-Min
Toppari, Jorma
Mykkänen, Juha
Ilonen, Jorma
Rich, Stephen S.
She, Jin-Xiong
Steck, Andrea K.
Krischer, Jeffrey
Role of Type 1 Diabetes–Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study
title Role of Type 1 Diabetes–Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study
title_full Role of Type 1 Diabetes–Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study
title_fullStr Role of Type 1 Diabetes–Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study
title_full_unstemmed Role of Type 1 Diabetes–Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study
title_short Role of Type 1 Diabetes–Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study
title_sort role of type 1 diabetes–associated snps on risk of autoantibody positivity in the teddy study
topic Genetics/Genomes/Proteomics/Metabolomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407865/
https://www.ncbi.nlm.nih.gov/pubmed/25422107
http://dx.doi.org/10.2337/db14-1497
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