Use of genetic variants related to antihypertensive drugs to inform on efficacy and side effects

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Title: Use of genetic variants related to antihypertensive drugs to inform on efficacy and side effects
Authors: Gill, D
Georgakis, MK
Koskeridis, F
Jiang, L
Wei, WQ
Theodoratou, E
Elliott, P
Denny, JC
Malik, R
Evangelou, E
Dehghan, A
Dichgans, M
Tzoulaki, I
Item Type: Journal Article
Abstract: Background: Drug effects can be investigated through natural variation in the genes for their protein targets. The current study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are amongst the most commonly used medications worldwide. Methods: Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure (SBP) at genome-wide significance. Mendelian randomization (MR) estimates for drug effects on coronary heart disease (CHD) and stroke risk were compared to randomized controlled trial (RCT) results. Phenome-wide association study (PheWAS) in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University Biobank (BioVU) and in observational analysis of the UK Biobank. Results: Suitable genetic proxies for angiotensin-converting-enzyme inhibitors (ACEIs), beta-blockers (BBs) and calcium channel blockers (CCBs) were identified. MR estimates for their effect on CHD and stroke risk respectively were comparable to results from RCTs against placebo. PheWAS in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio [OR] 1.02 per standard deviation increase, 95%CI 1.01-1.04), with a consistent estimate found in BioVU (OR 1.01, 95%CI 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to non-dihydropyridine CCBs (hazard ratio [HR] 1.49 considering thiazide diuretics as a comparator, 95%CI 1.04-2.14), but not dihydropyridine CCBs (HR 1.04, 95%CI 0.83-1.32). Conclusions: Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of non-dihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation.
Issue Date: 23-Jul-2019
Date of Acceptance: 2-May-2019
URI: http://hdl.handle.net/10044/1/70444
DOI: https://doi.org/10.1161/CIRCULATIONAHA.118.038814
ISSN: 0009-7322
Publisher: American Heart Association
Start Page: 270
End Page: 279
Journal / Book Title: Circulation
Volume: 140
Issue: 4
Copyright Statement: © 2019 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
UK DRI Ltd
Health Data Research Uk
Funder's Grant Number: RDF03
MR/L01341X/1
4050641385
Health Data Research UK
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Peripheral Vascular Disease
Cardiovascular System & Cardiology
antihypertensive drugs
Mendelian randomization analysis
CALCIUM-CHANNEL BLOCKERS
GENOME-WIDE ASSOCIATION
MENDELIAN RANDOMIZATION
DISEASE
HYPERTENSION
Mendelian randomization analysis
antihypertensive drugs
Cardiovascular System & Hematology
1103 Clinical Sciences
1102 Cardiorespiratory Medicine and Haematology
1117 Public Health and Health Services
Publication Status: Published
Online Publication Date: 2019-06-25
Appears in Collections:Faculty of Medicine
Epidemiology, Public Health and Primary Care



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