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A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
Noordam, Raymond; Sitlani, Colleen M; Avery, Christy L; Stewart, James D; Gogarten, Stephanie M; Wiggins, Kerri L; Trompet, Stella; Warren, Helen R; Sun, Fangui; Evans, Daniel S; Li, Xiaohui; Li, Jin; Smith, Albert V; Bis, Joshua C; Brody, Jennifer A; Busch, Evan L; Caulfield, Mark J; Chen, Yii-Der I; Cummings, Steven R; Cupples, L Adrienne; Duan, Qing; Franco, Oscar H; Méndez-Giráldez, Rául; Harris, Tamara B; Heckbert, Susan R; van Heemst, Diana; Hofman, Albert; Floyd, James S; Kors, Jan A; Launer, Lenore J; Li, Yun; Li-Gao, Ruifang; Lange, Leslie A; Lin, Henry J; de Mutsert, Renée; Napier, Melanie D; Newton-Cheh, Christopher; Poulter, Neil; Reiner, Alexander P; Rice, Kenneth M; Roach, Jeffrey; Rodriguez, Carlos J; Rosendaal, Frits R; Sattar, Naveed; Sever, Peter; Seyerle, Amanda A; Slagboom, P Eline; Soliman, Elsayed Z; Sotoodehnia, Nona; Stott, David J.
  • Noordam R; Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • Sitlani CM; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
  • Avery CL; Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Stewart JD; Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Gogarten SM; Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Wiggins KL; Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Trompet S; Department of Biostatistics, University of Washington, Seattle, Washington, USA.
  • Warren HR; Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Sun F; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
  • Evans DS; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
  • Li X; Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
  • Li J; NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
  • Smith AV; Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.
  • Bis JC; California Pacific Medical Center Research Institute, San Francisco, California, USA.
  • Brody JA; Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
  • Busch EL; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA.
  • Caulfield MJ; Icelandic Heart Association, Kopavogur, Iceland.
  • Chen YI; Faculty of Medicine, University of Iceland, Reykavik, Iceland.
  • Cummings SR; Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Cupples LA; Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Duan Q; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Franco OH; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
  • Méndez-Giráldez R; Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
  • Harris TB; NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
  • Heckbert SR; Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
  • van Heemst D; California Pacific Medical Center Research Institute, San Francisco, California, USA.
  • Hofman A; Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.
  • Floyd JS; Framingham Heart Study, Framingham, Massachusetts, USA.
  • Kors JA; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Launer LJ; Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • Li Y; Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Li-Gao R; Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, USA.
  • Lange LA; Department of Epidemiology, University of Washington, Seattle, Washington, USA.
  • Lin HJ; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
  • de Mutsert R; Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • Napier MD; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
  • Newton-Cheh C; Department of Medicine, University of Washington, Seattle, Washington, USA.
  • Poulter N; Department of Epidemiology, University of Washington, Seattle, Washington, USA.
  • Reiner AP; Department of Medical Informatics, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.
  • Rice KM; Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, USA.
  • Roach J; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Rodriguez CJ; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Rosendaal FR; Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Sattar N; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
  • Sever P; Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Seyerle AA; Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
  • Slagboom PE; Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
  • Soliman EZ; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
  • Sotoodehnia N; Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
  • Stott DJ; Framingham Heart Study, Framingham, Massachusetts, USA.
J Med Genet ; 54(5): 313-323, 2017 05.
Article en En | MEDLINE | ID: mdl-28039329
ABSTRACT

BACKGROUND:

Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tricyclic/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. METHODS AND

RESULTS:

We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45 706; n=1417 TCA users), African (n=10 235; n=296 TCA users) and Hispanic/Latino (n=13 808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval rs6737205 in BRE (ß=56.3, pinteraction=3.9e-9) and rs9830388 in UBE2E2 (ß=25.2, pinteraction=1.7e-8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (ß=9.3, pinteraction=2.55e-8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (pinteraction>0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries.

CONCLUSIONS:

Among Europeans, TCA interactions with variants in BRE and UBE2E2 were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Farmacogenética / Envejecimiento / Electrocardiografía / Estudio de Asociación del Genoma Completo / Corazón / Antidepresivos Tricíclicos Tipo de estudio: Prognostic_studies / Risk_factors_studies / Screening_studies Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Año: 2017 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Farmacogenética / Envejecimiento / Electrocardiografía / Estudio de Asociación del Genoma Completo / Corazón / Antidepresivos Tricíclicos Tipo de estudio: Prognostic_studies / Risk_factors_studies / Screening_studies Límite: Aged / Female / Humans / Male / Middle aged Idioma: En Año: 2017 Tipo del documento: Article