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Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry

The Pharmacogenomics Journal volume 20, pages 482–493 (2020)Cite this article

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Abstract

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10−8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

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Acknowledgements

This work was partially supported by National Institutes of Health National Heart, Lung, Blood Institute grants R01HL103612 (BMP) and K25HL121091 (YJS). Study-specific support included in the Supplementary Material.

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Authors and Affiliations

  1. Cardiovascular Division, Department of Medicine, Washington University, St. Louis, MO, USA

    L. de las Fuentes

  2. Division of Biostatistics, Washington University, St. Louis, MO, USA

    Y. J. Sung, K. Schwander & D. C. Rao

  3. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA

    C. M. Sitlani, J. C. Bis & K. L. Wiggins

  4. Gillings School of Global Public Health, Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA

    C. L. Avery, J. D. Stewart, T. Stürmer & E. A. Whitsel

  5. Cardiovascular Health Research Unit, Departments of Medicine and Biostatistics, University of Washington, Seattle, WA, USA

    T. M. Bartz

  6. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

    C. de Keyser, R. Ruiter, M. A. Ikram, A. Uitterlinden & B. Stricker

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

    D. S. Evans & S. R. Cummings

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

    X. Li, Y.-D. I. Chen, X. Guo, K. D. Taylor & J. I. Rotter

  9. Jackson Heart Study, Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA

    S. K. Musani & A. Correa

  10. Icelandic Heart Association, Kopavogur, Iceland

    A. V. Smith & V. Gudnason

  11. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    A. V. Smith & V. Gudnason

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

    F. Sun, H. Xu & L. A. Cupples

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

    S. Trompet & J. W. Jukema

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

    S. Trompet

  15. Dean’s Office, University of Kentucky College of Public Health, Lexington, KY, USA

    D. K. Arnett

  16. Section of Genomic Pediatrics, Department of Pediatrics, Medicine and Physiology, Medical College of Wisconsin, Milwaukee, WI, USA

    U. Broeckel

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

    E. L. Busch

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

    E. L. Busch

  19. Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA

    J. S. Floyd & N. Sotoodehnia

  20. Robertson Center for biostatistics, University of Glasgow, Glasgow, UK

    I. Ford

  21. Laboratory of Epidemiology and Population Sciences, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA

    T. B. Harris & L. J. Launer

  22. Department of Genetics, University of Colorado, Denver, Denver, CO, USA

    L. Lange

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

    A. P. Reiner

  24. School of Public Health, Department of Epidemiology, University of Washington, Seattle, WA, USA

    A. P. Reiner

  25. Cardiovascular Health Research Unit, Department of Epidemiology, University of Washington, Seattle, WA, USA

    N. L. Smith & S. R. Heckbert

  26. Seattle Epidemiologic Research and Information Center (ERIC), VA Cooperative Studies Program, VA Puget Sound Health Care System, Seattle, WA, USA

    N. L. Smith

  27. Cardiology, Department of Medicine, University of Washington, Seattle, WA, USA

    N. Sotoodehnia

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

    J. D. Stewart

  29. Institute of cardiovascular and medical sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom

    D. J. Stott

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

    T. Stürmer

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

    R. S. Vasan & L. A. Cupples

  32. Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    R. S. Vasan

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

    J. W. Jukema

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

    Y. Liu

  35. Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine, and Health Services, University of Washington, Seattle, WA, USA

    B. M. Psaty

  36. Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA

    B. M. Psaty

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

    J. G. Wilson

  38. School of Medicine, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA

    E. A. Whitsel

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  1. L. de las Fuentes
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Correspondence to L. de las Fuentes.

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de las Fuentes, L., Sung, Y.J., Sitlani, C.M. et al. Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry. Pharmacogenomics J 20, 482–493 (2020). https://doi.org/10.1038/s41397-019-0132-y

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