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Use of Genetic Variants Related to Antihypertensive Drugs to Inform on Efficacy and Side Effects.

Gill, D; Georgakis, MK; Koskeridis, F; Jiang, L; Feng, Q; Wei, W-Q; Theodoratou, E; Elliott, P; Denny, JC; Malik, R; et al. Gill, D; Georgakis, MK; Koskeridis, F; Jiang, L; Feng, Q; Wei, W-Q; Theodoratou, E; Elliott, P; Denny, JC; Malik, R; Evangelou, E; Dehghan, A; Dichgans, M; Tzoulaki, I (2019) Use of Genetic Variants Related to Antihypertensive Drugs to Inform on Efficacy and Side Effects. Circulation, 140 (4). pp. 270-279. ISSN 1524-4539 https://doi.org/10.1161/CIRCULATIONAHA.118.038814
SGUL Authors: Gill, Dipender Preet Singh

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Abstract

BACKGROUND: Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among 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 at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study 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, β-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01-1.04), with a consistent estimate found in BioVU (odds ratio, 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 nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04-2.14) but not dihydropyridine CCBs (hazard ratio, 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 nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation.

Item Type: Article
Additional Information: © 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, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Keywords: Mendelian randomization analysis, antihypertensive drugs, Antihypertensive Agents, Drug-Related Side Effects and Adverse Reactions, Humans, Pharmacogenomic Variants, Humans, Antihypertensive Agents, Drug-Related Side Effects and Adverse Reactions, Pharmacogenomic Variants, Cardiovascular System & Hematology, 1103 Clinical Sciences, 1102 Cardiorespiratory Medicine and Haematology, 1117 Public Health and Health Services
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Circulation
ISSN: 1524-4539
Language: eng
Dates:
DateEvent
23 July 2019Published
25 June 2019Published Online
2 May 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MR/L01341X/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
R01 GM120523NIGMS NIH HHSUNSPECIFIED
R01 HL133786NHLBI NIH HHSUNSPECIFIED
UNSPECIFIEDWellcome TrustUNSPECIFIED
R01 LM010685NLM NIH HHSUNSPECIFIED
C31250/A22804Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
UNSPECIFIEDDepartment of HealthUNSPECIFIED
666881Horizon 2020UNSPECIFIED
PubMed ID: 31234639
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/112805
Publisher's version: https://doi.org/10.1161/CIRCULATIONAHA.118.038814

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