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 Noordam; Jerome 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

doi:10.1093/ajh/hpz150

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

Am J Hypertens. 2019 Nov 15;32(12):1146-1153. doi: 10.1093/ajh/hpz150.

Authors

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.

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.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged
Antihypertensive Agents / adverse effects
Antihypertensive Agents / therapeutic use*
Black or African American / genetics
Blood Pressure / drug effects
Blood Pressure / genetics*
Case-Control Studies
DNA (Cytosine-5-)-Methyltransferases / genetics
DNA Methyltransferase 3A
DNA-Binding Proteins / genetics*
Drug Resistance / genetics*
Dystrophin-Associated Proteins / genetics
Europe / epidemiology
Female
Genetic Loci
Genome-Wide Association Study
Humans
Hypertension / drug therapy*
Hypertension / ethnology
Hypertension / genetics*
Hypertension / physiopathology
Male
Middle Aged
Myosin Heavy Chains / genetics
Myosin Type V / genetics
Neuropeptides / genetics
Pharmacogenetics
Pharmacogenomic Variants*
Polymorphism, Single Nucleotide*
Risk Assessment
Risk Factors
Transcription Factors / genetics*
United States / epidemiology
White People / genetics

Substances

Antihypertensive Agents
CASZ1 protein, human
DNA-Binding Proteins
DNMT3A protein, human
DTNB protein, human
Dystrophin-Associated Proteins
MYO5B protein, human
Neuropeptides
Transcription Factors
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A
Myosin Type V
Myosin Heavy Chains

Abstract

Publication types

MeSH terms

Substances

Grants and funding