■我们通过一项药物靶向孟德尔随机化研究,研究了抗高血压药物对预防心房颤动(AF)的潜在影响,以避免临床研究的潜在局限性。
■验证已发表的单核苷酸多态性(SNP)模拟12类降压药的作用,包括α-肾上腺素受体阻滞剂,肾上腺素能神经元阻滞剂,血管紧张素转换酶抑制剂,血管紧张素II受体阻滞剂,β-肾上腺素受体阻滞剂,中枢作用的抗高血压药物,钙通道阻滞剂,loop利尿剂,保钾利尿剂和盐皮质激素受体拮抗剂,肾素抑制剂,噻嗪类和相关利尿剂,使用了血管扩张剂。我们估计,通过它们相应的基因和蛋白质靶标,通过2个样本孟德尔随机分析,这些药物通过收缩压预防房颤的下游作用。SNP是从2个欧洲全基因组关联研究中提取的药物类别(n=317754;n=757601)和1个欧洲全基因组关联研究中提取的AF(n=1030836)。
■药物靶标孟德尔随机化分析支持通过α-肾上腺素受体阻滞剂降低收缩压每10mmHg的显着预防性因果效应(n=11个SNP;比值比[OR],0.34[95%CI,0.21-0.56];P=2.74×10-05),β-肾上腺素受体阻滞剂(n=17个SNP;OR,0.52[95%CI,0.35-0.78];P=1.62×10-03),钙通道阻滞剂(n=49SNPs;OR,0.50[95%CI,0.36-0.70];P=4.51×10-05),血管扩张剂(n=19个SNP;或,0.53[95%CI,0.34-0.84];P=7.03×10-03),和所有12类抗高血压药物的组合(n=158个SNP;OR,房颤风险为0.64[95%CI,0.54-0.77];P=8.50×10-07)。
■我们的结果表明,通过各种抗高血压药物的蛋白质靶点降低收缩压对于预防房颤似乎很有希望。我们的发现为未来的临床试验提供了信息,并对重新使用抗高血压药物预防房颤具有重要意义。
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: 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.