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Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval
Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the “missing heritability” of complex traits. Here, we describe four independent analyses in 33,781 participants of European ancestry from ten cohorts that were designed...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766418/ https://www.ncbi.nlm.nih.gov/pubmed/23459443 http://dx.doi.org/10.1038/tpj.2013.4 |
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author | Avery, Christy L. Sitlani, Colleen M. Arking, Dan E. Arnett, Donna K. Bis, Joshua C. Boerwinkle, Eric Buckley, Brendan M. Chen, Y.-D. Ida de Craen, Anton JM Eijgelsheim, Mark Enquobahrie, Daniel Evans, Daniel S. Ford, Ian Garcia, Melissa E. Gudnason, Vilmundur Harris, Tamara B. Heckbert, Susan R. Hochner, Hagit Hofman, Albert Hsueh, Wen-Chi Isaacs, Aaron Jukema, J. Wouter Knekt, Paul Kors, Jan A. Krijthe, Bouwe P. Kristiansson, Kati Laaksonen, Maarit Liu, Yongmei Li, Xiaohui MacFarlane, Peter W. Newton-Cheh, Christopher Nieminen, Markku S. Oostra, Ben A. Peloso, Gina M. Porthan, Kimmo Rice, Kenneth Rivadeneira, Fernando F. Rotter, Jerome I. Salomaa, Veikko Sattar, Naveed Siscovick, David S. Slagboom, P. Eline Smith, Albert V. Sotoodehnia, Nona Stott, David J. Stricker, Bruno H. Stürmer, Til Trompet, Stella Uitterlinden, Andre G. van Duijn, Cornelia M. Westendorp, Rudi GJ Witteman, Jacqueline C. Whitsel, Eric A. Psaty, Bruce M. |
author_facet | Avery, Christy L. Sitlani, Colleen M. Arking, Dan E. Arnett, Donna K. Bis, Joshua C. Boerwinkle, Eric Buckley, Brendan M. Chen, Y.-D. Ida de Craen, Anton JM Eijgelsheim, Mark Enquobahrie, Daniel Evans, Daniel S. Ford, Ian Garcia, Melissa E. Gudnason, Vilmundur Harris, Tamara B. Heckbert, Susan R. Hochner, Hagit Hofman, Albert Hsueh, Wen-Chi Isaacs, Aaron Jukema, J. Wouter Knekt, Paul Kors, Jan A. Krijthe, Bouwe P. Kristiansson, Kati Laaksonen, Maarit Liu, Yongmei Li, Xiaohui MacFarlane, Peter W. Newton-Cheh, Christopher Nieminen, Markku S. Oostra, Ben A. Peloso, Gina M. Porthan, Kimmo Rice, Kenneth Rivadeneira, Fernando F. Rotter, Jerome I. Salomaa, Veikko Sattar, Naveed Siscovick, David S. Slagboom, P. Eline Smith, Albert V. Sotoodehnia, Nona Stott, David J. Stricker, Bruno H. Stürmer, Til Trompet, Stella Uitterlinden, Andre G. van Duijn, Cornelia M. Westendorp, Rudi GJ Witteman, Jacqueline C. Whitsel, Eric A. Psaty, Bruce M. |
author_sort | Avery, Christy L. |
collection | PubMed |
description | Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the “missing heritability” of complex traits. Here, we describe four independent analyses in 33,781 participants of European ancestry from ten cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%), and QT prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-SNP interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (P(interaction)>5.0×10(−8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects. |
format | Online Article Text |
id | pubmed-3766418 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-37664182014-08-01 Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval Avery, Christy L. Sitlani, Colleen M. Arking, Dan E. Arnett, Donna K. Bis, Joshua C. Boerwinkle, Eric Buckley, Brendan M. Chen, Y.-D. Ida de Craen, Anton JM Eijgelsheim, Mark Enquobahrie, Daniel Evans, Daniel S. Ford, Ian Garcia, Melissa E. Gudnason, Vilmundur Harris, Tamara B. Heckbert, Susan R. Hochner, Hagit Hofman, Albert Hsueh, Wen-Chi Isaacs, Aaron Jukema, J. Wouter Knekt, Paul Kors, Jan A. Krijthe, Bouwe P. Kristiansson, Kati Laaksonen, Maarit Liu, Yongmei Li, Xiaohui MacFarlane, Peter W. Newton-Cheh, Christopher Nieminen, Markku S. Oostra, Ben A. Peloso, Gina M. Porthan, Kimmo Rice, Kenneth Rivadeneira, Fernando F. Rotter, Jerome I. Salomaa, Veikko Sattar, Naveed Siscovick, David S. Slagboom, P. Eline Smith, Albert V. Sotoodehnia, Nona Stott, David J. Stricker, Bruno H. Stürmer, Til Trompet, Stella Uitterlinden, Andre G. van Duijn, Cornelia M. Westendorp, Rudi GJ Witteman, Jacqueline C. Whitsel, Eric A. Psaty, Bruce M. Pharmacogenomics J Article Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the “missing heritability” of complex traits. Here, we describe four independent analyses in 33,781 participants of European ancestry from ten cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%), and QT prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-SNP interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (P(interaction)>5.0×10(−8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects. 2013-03-05 2014-02 /pmc/articles/PMC3766418/ /pubmed/23459443 http://dx.doi.org/10.1038/tpj.2013.4 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Avery, Christy L. Sitlani, Colleen M. Arking, Dan E. Arnett, Donna K. Bis, Joshua C. Boerwinkle, Eric Buckley, Brendan M. Chen, Y.-D. Ida de Craen, Anton JM Eijgelsheim, Mark Enquobahrie, Daniel Evans, Daniel S. Ford, Ian Garcia, Melissa E. Gudnason, Vilmundur Harris, Tamara B. Heckbert, Susan R. Hochner, Hagit Hofman, Albert Hsueh, Wen-Chi Isaacs, Aaron Jukema, J. Wouter Knekt, Paul Kors, Jan A. Krijthe, Bouwe P. Kristiansson, Kati Laaksonen, Maarit Liu, Yongmei Li, Xiaohui MacFarlane, Peter W. Newton-Cheh, Christopher Nieminen, Markku S. Oostra, Ben A. Peloso, Gina M. Porthan, Kimmo Rice, Kenneth Rivadeneira, Fernando F. Rotter, Jerome I. Salomaa, Veikko Sattar, Naveed Siscovick, David S. Slagboom, P. Eline Smith, Albert V. Sotoodehnia, Nona Stott, David J. Stricker, Bruno H. Stürmer, Til Trompet, Stella Uitterlinden, Andre G. van Duijn, Cornelia M. Westendorp, Rudi GJ Witteman, Jacqueline C. Whitsel, Eric A. Psaty, Bruce M. Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval |
title | Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval |
title_full | Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval |
title_fullStr | Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval |
title_full_unstemmed | Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval |
title_short | Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval |
title_sort | drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the qt interval |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766418/ https://www.ncbi.nlm.nih.gov/pubmed/23459443 http://dx.doi.org/10.1038/tpj.2013.4 |
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