Use of Genetic Variants Related to Antihypertensive Drugs to Inform on Efficacy and Side Effects
Use of Genetic Variants Related to Antihypertensive Drugs to Inform on Efficacy and Side Effects
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DOI：
10.1161/circulationaha.118.038814
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发表时间：
2019-07-23
期刊：
影响因子：
37.8
通讯作者：
Tzoulaki, Ioanna
中科院分区：
文献类型：
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作者：
Gill, Dipender;Georgakis, Marios K.;Tzoulaki, Ioanna
背景：药物作用可以通过其蛋白质靶基因的自然变异来研究。本研究旨在使用这种方法来探索抗高血压药物的潜在副作用和再利用潜力，这些药物是全球最常用的药物之一。研究方法：抗高血压药物类别效应的遗传代理被确定为在全基因组显著性上与收缩压相关的相应靶点的基因变异。将孟德尔随机化估计的药物对冠心病和中风风险的影响与随机对照试验结果进行比较。在英国生物库中进行了一项全表型关联研究，以确定潜在的副作用和再利用机会，并在范德比尔特大学生物库（BioVU）和英国生物库的观察分析中调查了结果。结果：确定了血管紧张素转换酶抑制剂、β受体阻滞剂和钙通道阻滞剂（CCB）的合适遗传代理。孟德尔随机化估计其对冠心病和中风风险的影响，分别与随机对照试验对安慰剂的结果相当。英国生物库中的一项全表型关联研究确定了CCB标准化遗传风险评分与憩室病风险增加的关联（比值比，1.02/标准差增加; 95%CI，1.01-1.04），在BioVU中发现了一致的估计值（比值比，1.01; 95%CI，1.00-1.02）。英国生物库中药物使用的考克斯回归分析表明，这种关联仅限于非二氢吡啶类CCB（风险比1.49，考虑噻嗪类利尿剂作为对照; 95% CI，1.04-2.14），而非二氢吡啶类CCB（风险比，1.04; 95% CI，0.83-1.32）。结论：遗传变异可用于探讨抗高血压药物的疗效和副作用。已确定的非二氢吡啶类CCB对憩室病风险的潜在影响可能具有临床意义，需要进一步研究。
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, beta-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.