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Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families

The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TE...

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Autores principales: Hippich, Markus, Beyerlein, Andreas, Hagopian, William A., Krischer, Jeffrey P., Vehik, Kendra, Knoop, Jan, Winker, Christiane, Toppari, Jorma, Lernmark, Åke, Rewers, Marian J., Steck, Andrea K., She, Jin-Xiong, Akolkar, Beena, Robertson, Catherine C., Onengut-Gumuscu, Suna, Rich, Stephen S., Bonifacio, Ezio, Ziegler, Anette-G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425872/
https://www.ncbi.nlm.nih.gov/pubmed/30655385
http://dx.doi.org/10.2337/db18-0882
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author Hippich, Markus
Beyerlein, Andreas
Hagopian, William A.
Krischer, Jeffrey P.
Vehik, Kendra
Knoop, Jan
Winker, Christiane
Toppari, Jorma
Lernmark, Åke
Rewers, Marian J.
Steck, Andrea K.
She, Jin-Xiong
Akolkar, Beena
Robertson, Catherine C.
Onengut-Gumuscu, Suna
Rich, Stephen S.
Bonifacio, Ezio
Ziegler, Anette-G.
author_facet Hippich, Markus
Beyerlein, Andreas
Hagopian, William A.
Krischer, Jeffrey P.
Vehik, Kendra
Knoop, Jan
Winker, Christiane
Toppari, Jorma
Lernmark, Åke
Rewers, Marian J.
Steck, Andrea K.
She, Jin-Xiong
Akolkar, Beena
Robertson, Catherine C.
Onengut-Gumuscu, Suna
Rich, Stephen S.
Bonifacio, Ezio
Ziegler, Anette-G.
author_sort Hippich, Markus
collection PubMed
description The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes–associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6–3.02]) and for diabetes (HR 2.92 [95% CI 2.05–4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.
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spelling pubmed-64258722020-04-01 Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families Hippich, Markus Beyerlein, Andreas Hagopian, William A. Krischer, Jeffrey P. Vehik, Kendra Knoop, Jan Winker, Christiane Toppari, Jorma Lernmark, Åke Rewers, Marian J. Steck, Andrea K. She, Jin-Xiong Akolkar, Beena Robertson, Catherine C. Onengut-Gumuscu, Suna Rich, Stephen S. Bonifacio, Ezio Ziegler, Anette-G. Diabetes Genetics/Genomes/Proteomics/Metabolomics The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes–associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6–3.02]) and for diabetes (HR 2.92 [95% CI 2.05–4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata. American Diabetes Association 2019-04 2019-01-17 /pmc/articles/PMC6425872/ /pubmed/30655385 http://dx.doi.org/10.2337/db18-0882 Text en © 2019 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders 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. More information is available at http://www.diabetesjournals.org/content/license.
spellingShingle Genetics/Genomes/Proteomics/Metabolomics
Hippich, Markus
Beyerlein, Andreas
Hagopian, William A.
Krischer, Jeffrey P.
Vehik, Kendra
Knoop, Jan
Winker, Christiane
Toppari, Jorma
Lernmark, Åke
Rewers, Marian J.
Steck, Andrea K.
She, Jin-Xiong
Akolkar, Beena
Robertson, Catherine C.
Onengut-Gumuscu, Suna
Rich, Stephen S.
Bonifacio, Ezio
Ziegler, Anette-G.
Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
title Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
title_full Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
title_fullStr Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
title_full_unstemmed Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
title_short Genetic Contribution to the Divergence in Type 1 Diabetes Risk Between Children From the General Population and Children From Affected Families
title_sort genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families
topic Genetics/Genomes/Proteomics/Metabolomics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425872/
https://www.ncbi.nlm.nih.gov/pubmed/30655385
http://dx.doi.org/10.2337/db18-0882
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