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

Marguerite R. Irvin, Colleen M. Sitlani, James S. Floyd, Bruce M. Psaty, Joshua C. Bis, Kerri L. Wiggins, Eric A. Whitsel, Til Sturmer, James Stewart, Laura Raffield, Fangui Sun, Ching Ti Liu, Hanfei Xu, Adrienne L. Cupples, Rikki M. Tanner, Peter Rossing, Albert Smith, Nuno R. Zilhão, Lenore J. Launer, Raymond NoordamJerome I. Rotter, Jie Yao, Xiaohui Li, Xiuqing Guo, Nita Limdi, Aishwarya Sundaresan, Leslie Lange, Adolfo Correa, David J. Stott, Ian Ford, J. Wouter Jukema, Vilmundur Gudnason, Dennis O. Mook-Kanamori, Stella Trompet, Walter Palmas, Helen R. Warren, Jacklyn N. Hellwege, Ayush Giri, Christopher O'Donnell, Adriana M. Hung, Todd L. Edwards, Tarunveer S. Ahluwalia, Donna K. Arnett, Christy L. Avery

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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.

Original languageEnglish
Pages (from-to)1146-1153
Number of pages8
JournalAmerican Journal of Hypertension
Issue number12
StatePublished - Nov 15 2019

Bibliographical note

Funding Information:
Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; 21Robertson Center for Biostatistics, University of Glasgow, Glasgow, UK; 22Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 23Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; 24Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands; 25Department of Medicine, Columbia University Medical Center, New York, New York, USA; 26William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 27National Institute for Health Research Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK; 28Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, Tennessee, USA; 29Division of Genetic Medicine, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA; 30Division 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; 31VA Boston Health Care System, Boston, Massachusetts, USA; 32Section of Cardiology and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; 33Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA; 34Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA; 35Deans Office, School of Public Health, University of Kentucky, Lexington, Kentucky, USA.

Funding Information:
The Prospective study of Pravastatin in the Elderly at Risk (PROSPER) study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J.  W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh frame-work program of the European Commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810).

Funding Information:
The Jackson Heart Study (JHS) is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), the Mississippi State Department of Health (HHSN268201800015I), and the University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute for Minority Health and Health Disparities (NIMHD). The authors also wish to thank the staffs and participants of the JHS. L.M.R. is funded by T32 HL12998. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.

Funding Information:
The Atherosclerosis Risk in Communities (ARIC) study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I), R01HL087641, 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.

Funding Information:
The Cardiovascular Health Study (CHS) was supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, HHSN268200960009C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086, and NHLBI Grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, U01HL130114, 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 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. J.S.F. was supported by K08HL116640.

Funding Information:
The authors of the Netherlands Epidemiology of Obesity (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. D.O.M.-K.  is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023).

Funding Information:
Multi-ethnic Study of Atherosclerosis (MESA) and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts HHSN268201500003I, 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, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, CA) and the Broad Institute of Harvard and MIT (Boston, MA) using the Affymetrix Genome-Wide Human SNP Array 6.0. Also supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, 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.

Funding Information:
The AfterEU study is the Danish part of the EURAGEDIC study, which was supported by the European Commission (contract QLG2-CT-2001–01669). The genotyping for this study was part of the Genetics of Diabetic Nephropathy (Gen DN) study, primarily funded by Juvenile Diabetes Research Foundation (JDRF) International Prime Award Number 17-2013-8. T.S.A. was also funded by the GenDN grant and acknowledges the same. Additionally, TSA was supported by internal funding from Steno Diabetes Center Copenhagen, Gentofte, Denmark and from the Novo Nordisk Foundation (Steno Collaborative 2018) Grant NNF18OC0052457 and acknowledged the same. No potential conflicts of interest relevant to this article were reported. The authors acknowledge the technical assistance of Tina R. Juhl, Anne G. Lundgaard, Berit R. Jensen, and Ulla M. Smidt. In addition, the authors thank Dr. Steve Rich, who was involved in genotyping from the University of Virginia, USA.

Funding Information:
The HyperGEN: Genetics of Left Ventricular Hypertrophy is ancillary to the Family Blood Pressure Program, 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, 471 U01HL054496 (MN); U01HL054473 (DCC); U01HL054495 (AL); U01HL054509 (NC).

Funding Information:
Age, Gene, Environment, Susceptibility—Reykjavik Study (AGES) has been funded by NIH contracts N01-AG-1-2100 and HHSN271201200022C, 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: 00-476 063). The researchers are indebted to the participants for their willingness to participate in the study.

Funding Information:
This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration and was supported by award I01BX003360 to A.M.H. This work was supported using resources and facilities of the VA Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457. J.N.H.  and A.G.  are supported by the Building Interdisciplinary Research Careers in Women’s Health Career Development Program grant K12HD043483 (PI: K.E. Hartmann). T.L.E. was supported by NIH/NHLBI grant HL121429.

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

Publisher Copyright:
© 2019 American Journal of Hypertension, Ltd. All rights reserved.


  • blood pressure
  • genome-wide association study
  • hypertension
  • severe hypertension
  • treatment-resistant hypertension

ASJC Scopus subject areas

  • Internal Medicine


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