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Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.
Avery, C L; Sitlani, C M; Arking, D E; Arnett, D K; Bis, J C; Boerwinkle, E; Buckley, B M; Ida Chen, Y-D; de Craen, A J M; Eijgelsheim, M; Enquobahrie, D; Evans, D S; Ford, I; Garcia, M E; Gudnason, V; Harris, T B; Heckbert, S R; Hochner, H; Hofman, A; Hsueh, W-C; Isaacs, A; Jukema, J W; Knekt, P; Kors, J A; Krijthe, B P; Kristiansson, K; Laaksonen, M; Liu, Y; Li, X; Macfarlane, P W; Newton-Cheh, C; Nieminen, M S; Oostra, B A; Peloso, G M; Porthan, K; Rice, K; Rivadeneira, F F; Rotter, J I; Salomaa, V; Sattar, N; Siscovick, D S; Slagboom, P E; Smith, A V; Sotoodehnia, N; Stott, D J; Stricker, B H; Stürmer, T; Trompet, S; Uitterlinden, A G; van Duijn, C.
Affiliation
  • Avery CL; Department of Epidemiology, Bank of America Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Sitlani CM; Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
  • Arking DE; McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Arnett DK; Department of Epidemiology, The University of Alabama at Birmingham, Birmingham, AL, USA.
  • Bis JC; Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
  • Boerwinkle E; Division of Epidemiology and Center for Human Genetics, The University of Texas Health Science Center, Houston, TX, USA.
  • Buckley BM; Department of Pharmacology and Therapeutics, University College Cork, Cork, UK.
  • Ida Chen YD; Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • de Craen AJ; Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
  • Eijgelsheim M; Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
  • Enquobahrie D; Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
  • Evans DS; California Pacific Medical Center Research Institute, San Francisco, CA, USA.
  • Ford I; Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
  • Garcia ME; Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
  • Gudnason V; Icelandic Heart Association, Kopavogur, Iceland.
  • Harris TB; Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
  • Heckbert SR; 1] Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA [2] Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • Hochner H; Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
  • Hofman A; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
  • Hsueh WC; Department of Medicine, University of California, San Francisco, CA, USA.
  • Isaacs A; 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Centre for Medical Systems Biology, Leiden, The Netherlands.
  • Jukema JW; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
  • Knekt P; THL-National Institute for Health and Welfare, Helsinki, Finland.
  • Kors JA; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
  • Krijthe BP; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
  • Kristiansson K; THL-National Institute for Health and Welfare, Helsinki, Finland.
  • Laaksonen M; THL-National Institute for Health and Welfare, Helsinki, Finland.
  • Liu Y; Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA.
  • Li X; Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Macfarlane PW; Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
  • Newton-Cheh C; 1] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA [2] Center for Human Genetic Research, Cardiovascular Research Center, Harvard Medical School, Boston, MA, USA [3] Massachusetts General Hospital, Boston, MA, USA.
  • Nieminen MS; Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
  • Oostra BA; 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Centre for Medical Systems Biology, Leiden, The Netherlands.
  • Peloso GM; 1] National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
  • Porthan K; Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
  • Rice K; Department of Biostatistics, University of Washington, Seattle, WA, USA.
  • Rivadeneira FF; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands [3] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
  • Rotter JI; Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Salomaa V; THL-National Institute for Health and Welfare, Helsinki, Finland.
  • Sattar N; BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, UK.
  • Siscovick DS; 1] Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA [2] Department of Epidemiology, University of Washington, Seattle, WA, USA.
  • Slagboom PE; Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
  • Smith AV; Icelandic Heart Association, Kopavogur, Iceland.
  • Sotoodehnia N; Division of Cardiology, University of Washington, Seattle, WA, USA.
  • Stott DJ; Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
  • Stricker BH; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands [3] Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands [4] Department of Internal Medicine, Erasmus Medica
  • Stürmer T; Department of Epidemiology, Bank of America Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • Trompet S; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
  • Uitterlinden AG; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands [3] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
  • van Duijn C; 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Centre for Medical Systems Biology, Leiden, The Netherlands.
Pharmacogenomics J ; 14(1): 6-13, 2014 Feb.
Article in En | MEDLINE | ID: mdl-23459443
ABSTRACT
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 10 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-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pharmacogenetics / Long QT Syndrome / Quantitative Trait, Heritable / Polymorphism, Single Nucleotide / Drug-Related Side Effects and Adverse Reactions / Gene-Environment Interaction Type of study: Health_economic_evaluation / Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Humans Language: En Journal: Pharmacogenomics J Journal subject: BIOLOGIA MOLECULAR / FARMACOLOGIA Year: 2014 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pharmacogenetics / Long QT Syndrome / Quantitative Trait, Heritable / Polymorphism, Single Nucleotide / Drug-Related Side Effects and Adverse Reactions / Gene-Environment Interaction Type of study: Health_economic_evaluation / Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies / Systematic_reviews Limits: Humans Language: En Journal: Pharmacogenomics J Journal subject: BIOLOGIA MOLECULAR / FARMACOLOGIA Year: 2014 Type: Article Affiliation country: United States