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Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry

The Pharmacogenomics Journal volume 19, pages 97–108 (2019)Cite this article

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Abstract

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10−8) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10−8; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

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Funding

Cardiovascular Health Study: 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 R01HL130114 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.

Jackson Heart Study: We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities.

Rotterdam Study: 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).

NEO Study: 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).

Heart and Vascular Health Studies: The Heart and Vascular Health Studies has been funded in part by NHLBI grants R01HL085251 and R01HL073410.

Atherosclerosis Risk in Communities Study: 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. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.

HyperGEN: Genetics of Left Ventricular Hypertrophy: The HyperGEN: Genetics of Left Ventricular Hypertrophy is ancillary to the Family Blood Pressure Program, http://clinicaltrials.gov/ct/show/NCT00005267. Funding sources included National Heart, Lung, and Blood Institute grant R01HL055673 and cooperative agreements (U01) with the National Heart, Lung, and Blood Institute: U01HL054471, U01HL54515 (UT); U01HL054472, U01HL054496 (MN); U01HL054473 (DCC); U01HL054495 (AL); U01HL054509 (NC).

AGES: Age, Gene, Environment, Susceptibility—Reykjavik Study: 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.

Author information

Authors and Affiliations

  1. Department of Epidemiology, University of Alabama, Birmingham, AL, USA

    Marguerite R. Irvin

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

    Colleen M. Sitlani

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

    Raymond Noordam

  4. Department of Internal Medicine, Section Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

    Raymond Noordam

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

    Christie L. Avery

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

    Joshua C. Bis

  7. Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA

    James S. Floyd

  8. Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, USA

    Jin Li

  9. Department of Neurology, University of Alabama, Birmingham, AL, USA

    Nita A. Limdi

  10. Department of Biostatistics, University of Alabama, Birmingham, AL, USA

    Vinodh Srinivasasainagendra

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

    James Stewart

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

    James Stewart

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

    Renée de Mutsert

  14. Department of Clinical Epidemiology and Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands

    Dennis O. Mook-Kanamori

  15. Department of Neurology, Wayne State University, Detroit, MI, USA

    Leonard Lipovich

  16. Center Molecular Medicine/Genetics, Wayne State University School of Medicine, Detroit, MI, USA

    Erica L. Kleinbrink

  17. Icelandic Heart Association, Kopavogur, Iceland, University of Iceland, Reykjavik, Iceland

    Albert Smith

  18. Departments of Biostatistics and Medicine, University of Washington, Seattle, WA, USA

    Traci M. Bartz

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

    Eric A. Whitsel

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

    Eric A. Whitsel

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

    Andre G. Uitterlinden

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

    Kerri L. Wiggins

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

    James G. Wilson

  24. School of Biomedical Informatics, University of Texas Health Sciences Center at Houston, Houston, TX, USA

    Degui Zhi

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

    Bruno H. Stricker

  26. Inspectorate of Health Care, Utrecht, The Netherlands

    Bruno H. Stricker

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

    Jerome I. Rotter

  28. College of Public Health, University of Kentucky, Lexington, KY, USA

    Donna K. Arnett

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

    Bruce M. Psaty

  30. Group Health Research Institute, Group Health Cooperatives, Seattle, WA, USA

    Bruce M. Psaty

  31. Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Leslie A. Lange

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  1. Marguerite R. Irvin
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  2. Colleen M. Sitlani
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  20. James G. Wilson
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  21. Degui Zhi
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Correspondence to Marguerite R. Irvin.

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The authors declare that they have no conflict of interest.

Ethical statement

All studies were approved by local ethics committees and all participants provided written informed consent. The ethics committees for the individual studies are: AGES: The National Bioethics Committee, Iceland; ARIC: University of North Carolina at Chapel Hill Office of Human Research Ethics; CHS: University of Washington Human Subjects Division IRB; HVH: Group Health Cooperative Human Subjects Review Committee; JHS: The Institutional Review Board of the University of Mississippi Medical Center; Medical Center Rotterdam Study: Medical Ethics Committee of the Erasmus Medical Center; HyperGEN: University of Alabama at Birmingham Office of Human Research Ethics; NEO: Ethical committee of the Leiden University Medical Center (LUMC).

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Irvin, M.R., Sitlani, C.M., Noordam, R. et al. Genome-wide meta-analysis of SNP-by9-ACEI/ARB and SNP-by-thiazide diuretic and effect on serum potassium in cohorts of European and African ancestry. Pharmacogenomics J 19, 97–108 (2019). https://doi.org/10.1038/s41397-018-0021-9

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