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

Dipender Gill, Marios K Georgakis, Fotios Koskeridis, Lan Jiang, Qiping Feng, Wei-Qi Wei, Evropi Theodoratou, Paul Elliott, Joshua C Denny, Rainer Malik, Evangelos Evangelou, Abbas Dehghan, Martin Dichgans, Ioanna Tzoulaki

Journal: Circulation 2020;140(4):270-279

PMID: 31234639

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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.

Address: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, United Kingdom (D.G., P.E., E.E., A.D., I.T.).; Institute for Stroke and Dementia Research, University Hospital (M.K.G., R.M., M.D.), Ludwig-Maximilians-Universität LMU, Munich, Germany.; Graduate School for Systemic Neurosciences (M.K.G.), Ludwig-Maximilians-Universität LMU, Munich, Germany.; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Greece (F.K., E.E., I.T.).; Division of Clinical Pharmacology, Department of Medicine (L.J., Q.F.), Vanderbilt University Medical Center, Nashville, TN.; Department of Biomedical Informatics (W.-Q.W., J.C.D.), Vanderbilt University Medical Center, Nashville, TN.; Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, United Kingdom (E.T.).; Medical Research Council-Public Health England Centre for Environment, School of Public Health, Imperial College London, United Kingdom (P.E., A.D., I.T.).; Imperial Biomedical Research Centre, Imperial College London and Imperial College NHS Healthcare Trust, UK (P.E.).; UK Dementia Research Institute at Imperial College London, UK (P.E., A.D., I.T.).; Health Data Research UK-London (P.E.).; Munich Cluster for Systems Neurology (SyNergy), Germany (M.D.).; German Center for Neurodegenerative Diseases (DZNE, Munich), Germany (M.D.).

DOI: 10.1161/CIRCULATIONAHA.118.038814