Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Jul 23;140(4):270-279.
doi: 10.1161/CIRCULATIONAHA.118.038814. Epub 2019 Jun 25.

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

Dipender Gill  1 , Marios K Georgakis  2   3 , Fotios Koskeridis  4 , Lan Jiang  5 , Qiping Feng  5 , Wei-Qi Wei  6 , Evropi Theodoratou  7 , Paul Elliott  1   8   9   10   11 , Joshua C Denny  6 , Rainer Malik  2 , Evangelos Evangelou  1   4 , Abbas Dehghan  1   8   10 , Martin Dichgans  2   12   13 , Ioanna Tzoulaki  1   4   8   10
Affiliations

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

Dipender Gill et al. Circulation. .

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.

Keywords: Mendelian randomization analysis; antihypertensive drugs.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
MR estimates for the effect of genetically lower systolic blood pressure through the ACE inhibitor, β-blocker, and calcium channel blocker variants, respectively, on risk of coronary heart disease and stroke, compared with randomized, controlled trial meta-analysis results.3 ACE indicates angiotensin-converting enzyme; IVW, inverse variance weighted; and MR, Mendelian randomization.
Figure 2.
Figure 2.
Phenome-wide association study of the standardized genetic risk score for angiotensin-converting enzyme inhibitors. The horizontal line depicts the 5% false-discovery rate threshold.
Figure 3.
Figure 3.
Phenome-wide association study of the standardized genetic risk score for β-blockers. The horizontal line depicts the 5% false-discovery rate threshold.
Figure 4.
Figure 4.
Phenome-wide association study of the standardized genetic risk score for calcium channel blockers. The horizontal line depicts the 5% false-discovery rate threshold.
Figure 5.
Figure 5.
Estimates for genetic association between calcium channel blockers and diverticulosis risk derived from PheWAS analyses in the UK Biobank and BioVU, respectively, and their fixed-effects pooled estimate. BioVU indicates Vanderbilt University Biobank; GRS, genetic risk score; and PheWAS, phenome-wide association study.
See this image and copyright information in PMC

Comment in

References

    1. Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, Alexander L, Estep K, Hassen Abate K, Akinyemiju TF, et al. Global burden of hypertension and systolic blood pressure of at least 110 to 115 mm Hg, 1990-2015. JAMA. 2017;317:165–182. doi: 10.1001/jama.2016.19043. - PubMed
    1. Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387:957–967. doi: 10.1016/S0140-6736(15)01225-8. - PubMed
    1. Wright JM, Musini VM, Gill R. First-line drugs for hypertension. Cochrane Database Syst Rev. 2018;4:CD001841. doi: 10.1002/14651858.CD001841.pub3. - PMC - PubMed
    1. Frieden TR. Evidence for health decision making - beyond randomized, controlled trials. N Engl J Med. 2017;377:465–475. doi: 10.1056/NEJMra1614394. - PubMed
    1. Tsang R, Colley L, Lynd LD. Inadequate statistical power to detect clinically significant differences in adverse event rates in randomized controlled trials. J Clin Epidemiol. 2009;62:609–616. doi: 10.1016/j.jclinepi.2008.08.005. - PubMed

Publication types

MeSH terms

Substances