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

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

Author information

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

PMID:
31545351
DOI:
10.1093/ajh/hpz150

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