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Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group

The Pharmacogenomics Journal volume 18, pages 127–135 (2018)Cite this article

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Abstract

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

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Acknowledgements

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.

Cardiovascular Health Study (CHS): This CHS research was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083 and 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. NS was supported by R01HL116747 and RO1HL111089. JSF was supported by K08HL116640.

Health, Aging, and Body Composition (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, National Institute on Aging.

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/Centers/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, National Institute of Neurological Disorders and Stroke and 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 26220/20054C, NCATS CTSI Grant UL1TR000124, and NIDDK Diabetes Research Center (DRC) Grant DK063491.

Jackson Heart Study (JHS): We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HSN268201300048C, HHSN268201300049C and 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): MESA and MESA SNP Health Association Resource (SHARe) are conducted and supported by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators. Support is provided by grants and contracts 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 RR-024156. Additional funding was supported in part by the Clinical Translational Science Institute Grant UL1RR033176 and is now at the National Center for Advancing Translational Sciences, CTSI Grant UL1TR000124. We also thank the other investigators, the staff and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.

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, Pat van Beelen, 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. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023).

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 program of the European commission (Grant No. 223004) and by the Netherlands Genomics Initiative (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; 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 Netherlands Organization for Scientific Research (NWO) (175.010.2005.011, 911.03.012) and Research Institute for Diseases in the Elderly (RIDE). This study was supported by The Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (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).

Women’s Health Initiative Clinical Trial (WHI CT): The Women’s Health Initiative clinical trials were funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through Contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C. All contributors to WHI science are listed at https://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Long%20List.pdf. ELB was supported in part by a grant from the National Cancer Institute (5T32CA009001). 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, US Department of Health and Human Services through cooperative agreement U01HG005152 (Reiner). All contributors to GARNET science are listed at https://www.genome.gov/27541119/genomics-and-randomized-trials-network-garnet/: The Modification of PM-Mediated Arrhythmogenesis in Populations was funded by the National Institute of Environmental Health Sciences, National Institutes of Health, US Department of Health and Human Services through Grant R01ES017794 (Whitsel). WHI SHARe: The SNP Health Association Resource project was funded by the National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contract N02HL64278 (Kooperberg). WHI WHIMS: The Women's Health Initiative Memory Study (WHIMS+) Genome-Wide Association Study was funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through Contract HHSN268201100046C (Anderson).

Author information

Author notes

  1. J S Floyd, C M Sitlani and C L Avery: These authors contributed equally to this work.

Authors and Affiliations

  1. Deparments of Epidemiology and Medicine, University of Washington, Seattle, WA, USA

    J S Floyd & N Sotoodehnia

  2. Department of Medicine, University of Washington, Seattle, WA, USA

    C M Sitlani, J A Brody, K L Wiggins & J C Bis

  3. Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA

    C L Avery, J D Stewart, M D Napier, T Stürmer & R Méndez-Giráldez

  4. Department of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands

    R Noordam & B H Stricker

  5. Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

    R Noordam

  6. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA

    X Li, H J Lin, K D Taylor, Y-DI Chen & J I Rotter

  7. Icelandic Heart Association, Kopavogur, Iceland

    A V Smith & V Gudnason

  8. Faculty of Medicine, University of Iceland, Reykavik, Iceland

    A V Smith & V Gudnason

  9. Department of Biostatistics, University of Washington, Seattle, WA, USA

    S M Gogarten, K F Kerr, K M Rice & C C Laurie

  10. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, CA, USA

    J Li

  11. Department of Internal Medicine, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands

    L Broer & A G Uitterlinden

  12. California Pacific Medical Center Research Institute, San Francisco, CA, USA

    D S Evans & S R Cummings

  13. Department of Cardiology and Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

    S Trompet

  14. Carolina Population Center, University of North Carolina, Chapel Hill, NC, USA

    J D Stewart

  15. Population Sciences Branch, National Heart Lung and Blood Institute, National Institutes of Health, Framingham, MA, USA

    J D Eicher & A D Johnson

  16. The Framingham Heart Study, Framingham, MA, USA

    J D Eicher, A D Johnson & L A Cupples

  17. Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA

    A A Seyerle

  18. Research Computing Center, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA

    J Roach, Q Duan & K C Wilhelmsen

  19. Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA

    L A Lange

  20. Division of Medical Genetics, Harbor-UCLA Medical Center, Torrance, CA, USA

    H J Lin

  21. Department of Medical Informatics, Erasmus MC - University Medical Center Rotterdam, Rotterdam, The Netherlands

    J A Kors

  22. Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, Bethesda, MD, USA

    T B Harris & L J Launer

  23. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    R Li-Gao, R de Mutsert, F R Rosendaal & D O Mook-Kanamori

  24. BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, UK

    N Sattar

  25. Center for Pharmacoepidemiology, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA

    T Stürmer

  26. Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Scotland, UK

    D J Stott

  27. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    E L Busch

  28. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    E L Busch

  29. Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, NC, USA

    E Z Soliman

  30. Department of Biostatistics, Computer Science, and Genetics, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA

    Y Li

  31. Department of Medical Statistics and Bioinformatics, Section of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    P E Slagboom

  32. The Renaissance Computing Institute, Chapel Hill, NC, USA

    K C Wilhelmsen

  33. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    A P Reiner

  34. Department of Epidemiology, University of Washington, Seattle, WA, USA

    A P Reiner & S R Heckbert

  35. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA

    R C Kaplan

  36. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands

    J W Jukema

  37. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

    J W Jukema

  38. Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands

    J W Jukema

  39. Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA

    Y Liu

  40. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands

    D O Mook-Kanamori

  41. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

    J G Wilson

  42. Departments of Epidemiology, Health Services, and Medicine, University of Washington, Seattle, WA, USA

    B M Psaty

  43. Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA

    B M Psaty

  44. Departments of Epidemiology and Medicine, University of North Carolina, Chapel Hill, Chapel Hill, NC, USA

    E A Whitsel

  45. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    L A Cupples

  46. Inspectorate of Health Care, Utrecht, The Netherlands

    B H Stricker

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  1. J S Floyd
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  2. C M Sitlani
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  3. C L Avery
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Corresponding author

Correspondence to J S Floyd.

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Competing interests

BMP serves on the DSMB of a clinical trial of a device funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. The other authors declare no conflict of interest.

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Floyd, J., Sitlani, C., Avery, C. et al. Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group. Pharmacogenomics J 18, 127–135 (2018). https://doi.org/10.1038/tpj.2016.90

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