Affiliation:
1. Department of Epidemiology (S.G., M.J.T., Z.L., B.H.C.S., J.W.D., M.A.I., M.K.), Erasmus MC, University Medical Center Rotterdam, The Netherlands.
2. Department of Cardiology (N.M.S.G.), Erasmus MC, University Medical Center Rotterdam, The Netherlands.
3. Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville (C.L.M.).
Abstract
BACKGROUND:
We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies.
METHODS:
Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836).
RESULTS:
Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21–0.56];
P
=2.74×10
−05
), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35–0.78];
P
=1.62×10
−03
), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36–0.70];
P
=4.51×10
−05
), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34–0.84];
P
=7.03×10
−03
), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54–0.77];
P
=8.50×10
−07
) on AF risk.
CONCLUSIONS:
Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention.
Publisher
Ovid Technologies (Wolters Kluwer Health)