Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group

Marguerite R Irvin¹, Colleen M Sitlani², James S Floyd², Bruce M Psaty^{2

3

4

5}, Joshua C Bis², Kerri L Wiggins², Eric A Whitsel^{6

7}, Til Sturmer⁷, James Stewart⁷, Laura Raffield⁸, Fangui Sun⁹, Ching-Ti Liu⁹, Hanfei Xu⁹, Adrienne L Cupples⁹, Rikki M Tanner¹, Peter Rossing¹⁰, Albert Smith^{11

12}, Nuno R Zilhão¹¹, Lenore J Launer¹³, Raymond Noordam¹⁴, Jerome I Rotter¹⁵, Jie Yao¹⁵, Xiaohui Li¹⁵, Xiuqing Guo¹⁵, Nita Limdi¹⁶, Aishwarya Sundaresan¹⁷, Leslie Lange¹⁸, Adolfo Correa¹⁹, David J Stott²⁰, Ian Ford²¹, J Wouter Jukema²², Vilmundur Gudnason^{23

24}, Dennis O Mook-Kanamori¹⁴, Stella Trompet¹⁴, Walter Palmas²⁵, Helen R Warren^{26

27}, Jacklyn N Hellwege^{28

29}, Ayush Giri^{28

30}, Christopher O'donnell^{31

32}, Adriana M Hung^{28

33}, Todd L Edwards^{28

34}, Tarunveer S Ahluwalia^{1

10}, Donna K Arnett³⁵, Christy L Avery⁷

Affiliations

¹ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
³ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
⁴ Department of Health Services, University of Washington, Seattle, Washington, USA.
⁵ Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
⁶ Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
⁷ Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
⁸ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
⁹ Department of Biostatistics, Boston University, Boston, Maryland, USA.
¹⁰ Steno Diabetes Center Copenhagen, Gentofte, Denmark.
¹¹ Icelandic Heart Association, Kopavogur, Iceland.
¹² University of Iceland, Reykjavik, Iceland.
¹³ Laboratory of Epidemiology and Population Science, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.
¹⁴ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁵ Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.
¹⁶ Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹⁷ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹⁸ Department of Medicine, University of Colorado-Denver, Aurora, Colorado, USA.
¹⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
²⁰ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
²¹ Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
²² Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
²³ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
²⁴ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ Department of Medicine, Columbia University Medical Center, New York, New York, USA.
²⁶ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
²⁷ National Institute for Health Research Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
²⁸ Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, Tennessee, USA.
²⁹ Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³⁰ Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³¹ VA Boston Health Care System, Boston, Massachusetts, USA.
³² Section of Cardiology and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³³ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³⁴ Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³⁵ Deans Office, School of Public Health, University of Kentucky, Lexington, Kentucky, USA.

PMID: 31545351
PMCID: PMC6856621
DOI: 10.1093/ajh/hpz150

Multicenter Study

Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group

Marguerite R Irvin et al. Am J Hypertens. 2019.

. 2019 Nov 15;32(12):1146-1153.

doi: 10.1093/ajh/hpz150.

Authors

Affiliations

¹ Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
² Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
³ Department of Epidemiology, University of Washington, Seattle, Washington, USA.
⁴ Department of Health Services, University of Washington, Seattle, Washington, USA.
⁵ Kaiser Permanente Washington Health Research Institute, Seattle, Washington, USA.
⁶ Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
⁷ Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
⁸ Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, USA.
⁹ Department of Biostatistics, Boston University, Boston, Maryland, USA.
¹⁰ Steno Diabetes Center Copenhagen, Gentofte, Denmark.
¹¹ Icelandic Heart Association, Kopavogur, Iceland.
¹² University of Iceland, Reykjavik, Iceland.
¹³ Laboratory of Epidemiology and Population Science, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.
¹⁴ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
¹⁵ Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.
¹⁶ Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹⁷ Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹⁸ Department of Medicine, University of Colorado-Denver, Aurora, Colorado, USA.
¹⁹ Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
²⁰ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
²¹ Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK.
²² Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
²³ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
²⁴ Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ Department of Medicine, Columbia University Medical Center, New York, New York, USA.
²⁶ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
²⁷ National Institute for Health Research Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK.
²⁸ Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, Tennessee, USA.
²⁹ Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³⁰ Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³¹ VA Boston Health Care System, Boston, Massachusetts, USA.
³² Section of Cardiology and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³³ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³⁴ Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³⁵ Deans Office, School of Public Health, University of Kentucky, Lexington, Kentucky, USA.

PMID: 31545351
PMCID: PMC6856621
DOI: 10.1093/ajh/hpz150

Abstract

Background: Only a handful of genetic discovery efforts in apparent treatment-resistant hypertension (aTRH) have been described.

Methods: We conducted a case-control genome-wide association study of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic BP ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg) or 4 or more medication classes regardless of BP control (nEA = 931, nAA = 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14,210, nAA = 2,480) and had systolic BP/diastolic BP < 140/90 mm Hg. Treatment-responsive controls (nEA = 5,266, nAA = 1,817) had BP at goal (<140/90 mm Hg), while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site, and principal components for ancestry to examine the association of single-nucleotide polymorphisms with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL.

Results: The known hypertension locus, CASZ1, was a top finding among EAs (P = 1.1 × 10-8) and in the race-combined analysis (P = 1.5 × 10-9) using the normotensive control group (rs12046278, odds ratio = 0.71 (95% confidence interval: 0.6-0.8)). Single-nucleotide polymorphisms in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls.

Conclusion: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

Keywords: blood pressure; genome-wide association study; hypertension; severe hypertension; treatment-resistant hypertension.

PubMed Disclaimer

References

1. Egan BM, Zhao Y, Axon RN, Brzezinski WA, Ferdinand KC. Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. Circulation 2011; 124:1046–1058. - PMC - PubMed
1. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR, Egan BM, Flack JM, Gidding SS, Judd E, Lackland DT, Laffer CL, Newton-Cheh C, Smith SM, Taler SJ, Textor SC, Turan TN, White WB; American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council.Resistant hypertension: detection, evaluation, and management: a Scientific Statement From the American Heart Association . Hypertension 2018; 72:e53–e90. - PMC - PubMed
1. Irvin MR, Booth JN 3rd, Shimbo D, Lackland DT, Oparil S, Howard G, Safford MM, Muntner P, Calhoun DA. Apparent treatment-resistant hypertension and risk for stroke, coronary heart disease, and all-cause mortality. J Am Soc Hypertens 2014; 8:405–413. - PMC - PubMed
1. Lynch AI, Irvin MR, Davis BR, Ford CE, Eckfeldt JH, Arnett DK. Genetic and adverse health outcome associations with treatment resistant hypertension in GenHAT. Int J Hypertens 2013; 2013:578578. - PMC - PubMed
1. Dumitrescu L, Ritchie MD, Denny JC, El Rouby NM, McDonough CW, Bradford Y, Ramirez AH, Bielinski SJ, Basford MA, Chai HS, Peissig P, Carrell D, Pathak J, Rasmussen LV, Wang X, Pacheco JA, Kho AN, Hayes MG, Matsumoto M, Smith ME, Li R, Cooper-DeHoff RM, Kullo IJ, Chute CG, Chisholm RL, Jarvik GP, Larson EB, Carey D, McCarty CA, Williams MS, Roden DM, Bottinger E, Johnson JA, de Andrade M, Crawford DC. Genome-wide study of resistant hypertension identified from electronic health records. PLoS One 2017; 12:e0171745. - PMC - PubMed

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group

Affiliations

Genome-Wide Association Study of Apparent Treatment-Resistant Hypertension in the CHARGE Consortium: The CHARGE Pharmacogenetics Working Group

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous