Raymond Noordam1,2, Colleen M Sitlani3, Christy L Avery4, James D Stewart4,5, Stephanie M Gogarten6, Kerri L Wiggins3, Stella Trompet2,7, Helen R Warren8,9, Fangui Sun10, Daniel S Evans11, Xiaohui Li12, Jin Li13, Albert V Smith14,15, Joshua C Bis3, Jennifer A Brody3, Evan L Busch16,17, Mark J Caulfield8,9, Yii-Der I Chen12, Steven R Cummings11, L Adrienne Cupples10,18, Qing Duan19, Oscar H Franco1, Rául Méndez-Giráldez4, Tamara B Harris20, Susan R Heckbert21, Diana van Heemst2, Albert Hofman1,16, James S Floyd3,21, Jan A Kors22, Lenore J Launer20, Yun Li19,23,24, Ruifang Li-Gao25, Leslie A Lange19, Henry J Lin12,26, Renée de Mutsert25, Melanie D Napier4, Christopher Newton-Cheh18,27,28, Neil Poulter29, Alexander P Reiner21,30, Kenneth M Rice6, Jeffrey Roach31, Carlos J Rodriguez32,33, Frits R Rosendaal25, Naveed Sattar34, Peter Sever29, Amanda A Seyerle4, P Eline Slagboom35, Elsayed Z Soliman36, Nona Sotoodehnia3,21, David J Stott37, Til Stürmer4,38, Kent D Taylor12, Timothy A Thornton6, André G Uitterlinden39, Kirk C Wilhelmsen19,40, James G Wilson41, Vilmundur Gudnason14,15, J Wouter Jukema7,42,43, Cathy C Laurie6, Yongmei Liu44, Dennis O Mook-Kanamori25,45,46, Patricia B Munroe8,9, Jerome I Rotter12, Ramachandran S Vasan18,47, Bruce M Psaty3,21,48,49, Bruno H Stricker1,50, Eric A Whitsel4,51. 1. Department of Epidemiology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands. 2. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands. 3. Department of Medicine, University of Washington, Seattle, Washington, USA. 4. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA. 5. Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina, USA. 6. Department of Biostatistics, University of Washington, Seattle, Washington, USA. 7. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. 8. Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK. 9. NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine, Queen Mary University of London, London, UK. 10. Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA. 11. California Pacific Medical Center Research Institute, San Francisco, California, USA. 12. Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA. 13. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA. 14. Icelandic Heart Association, Kopavogur, Iceland. 15. Faculty of Medicine, University of Iceland, Reykavik, Iceland. 16. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. 17. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. 18. Framingham Heart Study, Framingham, Massachusetts, USA. 19. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA. 20. Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, USA. 21. Department of Epidemiology, University of Washington, Seattle, Washington, USA. 22. Department of Medical Informatics, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands. 23. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA. 24. Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, USA. 25. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 26. Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA. 27. Cardiovascular Research Center & Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA. 28. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. 29. International Centre for Circulatory Health, Imperial College London, London, UK. 30. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. 31. Research Computing Center, University of North Carolina, Chapel Hill, North Carolina, USA. 32. Department of Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. 33. Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. 34. Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK. 35. Department of Medical Statistics and Bioinformatics, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 36. Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. 37. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. 38. Center of Pharmacoepidemiology, Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA. 39. Department of Internal Medicine, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands. 40. The Renaissance Computing Institute, Chapel Hill, North Carolina, USA. 41. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA. 42. Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands. 43. Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands. 44. Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest University, Winston-Salem, North Carolina, USA. 45. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands. 46. Department of BESC, Epidemiology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. 47. Department of Medicine, School of Medicine, Boston University, Boston, Massachusetts, USA. 48. Department of Health Services, University of Washington, Seattle, Washington, USA. 49. Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA. 50. Inspectorate of Health Care, Utrecht, The Netherlands. 51. Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
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 (β=56.3, pinteraction=3.9e-9) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e-8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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 (β=56.3, pinteraction=3.9e-9) and rs9830388 in UBE2E2 (β=25.2, pinteraction=1.7e-8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β=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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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Authors: J Gustav Smith; Christy L Avery; Daniel S Evans; Michael A Nalls; Yan A Meng; Erin N Smith; Cameron Palmer; Toshiko Tanaka; Reena Mehra; Anne M Butler; Taylor Young; Sarah G Buxbaum; Kathleen F Kerr; Gerald S Berenson; Renate B Schnabel; Guo Li; Patrick T Ellinor; Jared W Magnani; Wei Chen; Joshua C Bis; J David Curb; Wen-Chi Hsueh; Jerome I Rotter; Yongmei Liu; Anne B Newman; Marian C Limacher; Kari E North; Alexander P Reiner; P Miguel Quibrera; Nicholas J Schork; Andrew B Singleton; Bruce M Psaty; Elsayed Z Soliman; Allen J Solomon; Sathanur R Srinivasan; Alvaro Alonso; Robert Wallace; Susan Redline; Zhu-Ming Zhang; Wendy S Post; Alan B Zonderman; Herman A Taylor; Sarah S Murray; Luigi Ferrucci; Dan E Arking; Michele K Evans; Ervin R Fox; Nona Sotoodehnia; Susan R Heckbert; Eric A Whitsel; Christopher Newton-Cheh Journal: Circ Cardiovasc Genet Date: 2012-11-19
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