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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
  1. Raymond Noordam1,2,
  2. Colleen M Sitlani3,
  3. Christy L Avery4,
  4. James D Stewart4,5,
  5. Stephanie M Gogarten6,
  6. Kerri L Wiggins3,
  7. Stella Trompet2,7,
  8. Helen R Warren8,9,
  9. Fangui Sun10,
  10. Daniel S Evans11,
  11. Xiaohui Li12,
  12. Jin Li13,
  13. Albert V Smith14,15,
  14. Joshua C Bis3,
  15. Jennifer A Brody3,
  16. Evan L Busch16,17,
  17. Mark J Caulfield8,9,
  18. Yii-Der I Chen12,
  19. Steven R Cummings11,
  20. L Adrienne Cupples10,18,
  21. Qing Duan19,
  22. Oscar H Franco1,
  23. Rául Méndez-Giráldez4,
  24. Tamara B Harris20,
  25. Susan R Heckbert21,
  26. Diana van Heemst2,
  27. Albert Hofman1,16,
  28. James S Floyd3,21,
  29. Jan A Kors22,
  30. Lenore J Launer20,
  31. Yun Li19,23,24,
  32. Ruifang Li-Gao25,
  33. Leslie A Lange19,
  34. Henry J Lin12,26,
  35. Renée de Mutsert25,
  36. Melanie D Napier4,
  37. Christopher Newton-Cheh18,27,28,
  38. Neil Poulter29,
  39. Alexander P Reiner21,30,
  40. Kenneth M Rice6,
  41. Jeffrey Roach31,
  42. Carlos J Rodriguez32,33,
  43. Frits R Rosendaal25,
  44. Naveed Sattar34,
  45. Peter Sever29,
  46. Amanda A Seyerle4,
  47. P Eline Slagboom35,
  48. Elsayed Z Soliman36,
  49. Nona Sotoodehnia3,21,
  50. David J Stott37,
  51. Til Stürmer4,38,
  52. Kent D Taylor12,
  53. Timothy A Thornton6,
  54. André G Uitterlinden39,
  55. Kirk C Wilhelmsen19,40,
  56. James G Wilson41,
  57. Vilmundur Gudnason14,15,
  58. J Wouter Jukema7,42,43,
  59. Cathy C Laurie6,
  60. Yongmei Liu44,
  61. Dennis O Mook-Kanamori25,45,46,
  62. Patricia B Munroe8,9,
  63. Jerome I Rotter12,
  64. Ramachandran S Vasan18,47,
  65. Bruce M Psaty3,21,48,49,
  66. Bruno H Stricker1,50,
  67. Eric A Whitsel4,51
  1. 1Department of Epidemiology, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
  2. 2Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Department of Medicine, University of Washington, Seattle, Washington, USA
  4. 4Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  5. 5Carolina Population Center, University of North Carolina, Chapel Hill, North Carolina, USA
  6. 6Department of Biostatistics, University of Washington, Seattle, Washington, USA
  7. 7Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
  8. 8Department of Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, UK
  9. 9NIHR Barts Cardiovascular Biomedical Research Unit, Barts and The London School of Medicine, Queen Mary University of London, London, UK
  10. 10Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA
  11. 11California Pacific Medical Center Research Institute, San Francisco, California, USA
  12. 12Institute for Translational Genomics and Population Sciences and Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
  13. 13Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
  14. 14Icelandic Heart Association, Kopavogur, Iceland
  15. 15Faculty of Medicine, University of Iceland, Reykavik, Iceland
  16. 16Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
  17. 17Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
  18. 18Framingham Heart Study, Framingham, Massachusetts, USA
  19. 19Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA
  20. 20Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, Maryland, USA
  21. 21Department of Epidemiology, University of Washington, Seattle, Washington, USA
  22. 22Department of Medical Informatics, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
  23. 23Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA
  24. 24Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, USA
  25. 25Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  26. 26Division of Medical Genetics, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA
  27. 27Cardiovascular Research Center & Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA
  28. 28Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
  29. 29International Centre for Circulatory Health, Imperial College London, London, UK
  30. 30Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  31. 31Research Computing Center, University of North Carolina, Chapel Hill, North Carolina, USA
  32. 32Department of Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  33. 33Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  34. 34Faculty of Medicine, BHF Glasgow Cardiovascular Research Centre, Glasgow, UK
  35. 35Department of Medical Statistics and Bioinformatics, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
  36. 36Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
  37. 37Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
  38. 38Center of Pharmacoepidemiology, Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
  39. 39Department of Internal Medicine, Erasmus MC—University Medical Center Rotterdam, Rotterdam, The Netherlands
  40. 40The Renaissance Computing Institute, Chapel Hill, North Carolina, USA
  41. 41Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, USA
  42. 42Durrer Center for Cardiogenetic Research, Amsterdam, The Netherlands
  43. 43Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
  44. 44Division of Public Health Sciences, Department of Epidemiology and Prevention, Wake Forest University, Winston-Salem, North Carolina, USA
  45. 45Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands
  46. 46Department of BESC, Epidemiology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
  47. 47Department of Medicine, School of Medicine, Boston University, Boston, Massachusetts, USA
  48. 48Department of Health Services, University of Washington, Seattle, Washington, USA
  49. 49Group Health Research Institute, Group Health Cooperative, Seattle, Washington, USA
  50. 50Inspectorate of Health Care, Utrecht, The Netherlands
  51. 51Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
  1. Correspondence to Dr. Bruno H Stricker, Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands; b.stricker{at}erasmusmc.nl

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.

  • Genome-wide
  • drug-gene interaction
  • tri/tetracyclic antidepressants
  • RR interval
  • QT interval electrocardiography

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Footnotes

  • RN, CMS and CLA contributed equally.

  • BMP, BHS and EAW jointly directed this work.

  • Contributors Writing and analysis group: RN, CMS, CLA, BMP, BHS and EAW. All authors contributed to the research, commented on the draft versions of the manuscript and approved the final version before submission.

  • Funding Age, Gene/Environment Susceptibility—Reykjavik Study (AGES): This study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00-063. The researchers are indebted to the participants for their willingness to participate in the study. Atherosclerosis Risk in Communities (ARIC): The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute Contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute Contract U01HG004402 and National Institutes of Health Contract HHSN268200625226C. We thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant No. UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Anglo-Scandinavian Cardiac Outcomes Trial UK (ASCOT): This trial was funded by an investigator-initiated grant from Pfizer, USA. The study was investigator led and was conducted, analysed and reported independently of the company. Genotyping was funded by the National Institutes for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Cardiovascular Biomedical Research Unit at Barts and the London, Queen Mary University of London (QMUL), the NIHR Biomedical Research Centre at Imperial College, the International Centre for Circulatory Health Charity and the Medical Research Council through G952010. On behalf of the ASCOT investigators, we thank all ASCOT trial participants, physicians, nurses and practices in the participating countries for their important contribution to the study. Helen R Warren, Mark J Caulfield and Patricia B Munrow wish to acknowledge support from the NIHR Cardiovascular Biomedical Unit at Barts and the London, QMUL, UK. Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393 and R01HL085251 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124 and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Framingham Heart Study (FHS): FHS work was supported by the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine (Contract No. N01-HC-25195 and Contract No. HHSN268201500001I), its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278), based on analyses by FHS investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II), funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Additional support for these analyses was provided by R01HL103612 (PI Psaty, subcontract PI, Vasan). Measurement of the Gen 3 ECGs was supported by grants from the Doris Duke Charitable Foundation and the Burroughs Wellcome Fund (Newton-Cheh) and the NIH (HL080025, Newton-Cheh). Health, Aging and Body Composition Study (Health ABC): This research was supported by NIA Contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA Grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract No. HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, NIA. Hispanic Community Health Study/Study of Latinos (HCHS/SOL): We thank the participants and staff of the HCHS/SOL study for their contributions to this study. The baseline examination of HCHS/SOL was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236) and San Diego State University (N01-HC65237). The following Institutes/Centres/Offices contributed to the first phase of HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Diabetes and Digestive and Kidney Diseases, NINDS, NIH Institution-Office of Dietary Supplements. The Genetic Analysis Center at University of Washington was supported by NHLBI and NIDCR contracts (HHSN268201300005C AM03 and MOD03). Genotyping efforts were supported by NHLBI HSN 26 220/20054C, NCATS CTSI grant UL1TR000124, and NIDDK DRC grant DK063491. Jackson Heart Study (JHS): We thank the JHS participants and staff for their contributions to this work. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung and Blood Institute and the National Institute on Minority Health and Health Disparities. Multi-Ethnic Study of Atherosclerosis (MESA): This research was supported by contracts HHSN2682015000031, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169 and by grants UL1-TR-000040, UL1-TR-001079, and UL1-RR-025005 from NCRR. Funding for MESA Family was provided by grants R01-HL-071205, R01-HL-071051, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258 and R01-HL-071259, and by UL1-RR-025005 and UL1RR033176 from NCRR. Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124 and the National Institute of Diabetes and Digestive and Kidney Disease DRC grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Further information can be found at http://www.mesa-nhlbi.org and http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000209.v13.p3. Netherlands Epidemiology of Obesity (NEO): The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants and all research nurses for collection of the data. We thank the NEO study group, Petra Noordijk and Ingeborg de Jonge for the coordination, lab and data management of the NEO study. The genotyping in the NEO study was supported by the Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): The PROSPER study was supported by an investigator initiated grant obtained from Bristol-Myers Squibb. Professor Dr J W Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (Grant No. 2001 D 032). Support for genotyping was provided by the seventh framework programme of the European commission (Grant No. 223004) and by the Netherlands Genomics Initiative (NGI) (Netherlands Consortium for Healthy Aging Grant 050-060-810). Rotterdam Study (RS): The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; The Netherlands Organization for Scientific Research (NWO); The Netherlands Organization for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly; The Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission and the Municipality of Rotterdam. Support for genotyping was provided by the NWO (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was supported by The NGI/NWO Project No. 050-060-810. This collaborative effort was supported by an award from the National Heart, Lung and Blood Institute (R01-HL-103612, PI BMP). CLA was supported in part by Grant R00-HL-098458 from the National Heart, Lung and Blood Institute. Women's Health Initiative (WHI): WHI programme is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, the US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C and HHSN268201600004C. The authors thank the WHI investigators and staff for their dedication, and the study participants for making the programme possible. A full listing of WHI investigators can be found at: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf. WHI—GWAS of Treatment Response in Randomized Clinical Trials (WHI GARNET): Within the Genomics and Randomized Trials Network, a GWAS of Hormone Treatment and CVD and Metabolic Outcomes in the WHI was funded by the National Human Genome Research Institute, National Institutes of Health, the US Department of Health and Human Services through cooperative agreement U01HG005152 (Reiner). All contributors to GARNET science are listed at https://www.garnetstudy.org/Home. ELB was supported in part by a grant from the National Cancer Institute (5T32CA009001). WHI—Modification of Particulate Matter-Mediated Arrythmogenesis in Populations (WHI MOPMAP): The WHI MOPMAP was funded by the National Institute of Environmental Health Sciences, National Institutes of Health, the US Department of Health and Human Services through grant R01ES017794 (Whitsel). WHI—The SNP Health Associations Resource (WHI SHARe): The SNP Health Association Resource project was funded by the National Heart, Lung and Blood Institute, National Institutes of Health, the US Department of Health and Human Services through contract N02HL64278 (Kooperberg).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval All studies were approved by Local Ethics Committees.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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