{"title":"利用遗传学和蛋白质组学评估降压药在人类长寿中的作用及其潜在途径：孟德尔随机研究。","authors":"Bohan Fan, Jie V Zhao","doi":"10.1093/ehjcvp/pvae038","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Antihypertensive drugs are known to lower cardiovascular mortality, but the role of different types of antihypertensive drugs in lifespan has not been clarified. Moreover, the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>To minimize confounding, we used Mendelian randomization to assess the role of different antihypertensive drug classes in longevity and examined the pathways via proteins. Genetic variants associated with systolic blood pressure (SBP) corresponding to drug target genes were used as genetic instruments. The genetic associations with lifespan were obtained from a large genome-wide association study including 1 million European participants from UK Biobank and LifeGen. For significant antihypertensive drug classes, we performed sex-specific analysis, drug-target analysis and colocalization. To examine the mediation pathways, we assessed the associations of 2291 plasma proteins with lifespan, and examined the associations of drug classes with the proteins affecting lifespan.</p><p><strong>Results: </strong>After correcting for multiple testing, genetically proxied beta-blockers (BBs), calcium channel blockers (CCBs) and vasodilators were related to longer life years (BBs: 2.03, 95% CI 0.78 to 3.28 per 5-mmHg reduction in SBP, CCBs: 3.40, 95% CI 1.47 to 5.33, and vasodilators: 2.92, 95% CI 1.08 to 4.77). The beneficial effects of BBs and CCBs were more obvious in men. ADRB1, CACNA2D2, CACNB3, CPT1A, CPT2, and EDNRA genes were related to extended lifespan with CPT2 further supported by colocalization evidence. 86 proteins were related to lifespan, of which 4 proteins were affected by CCBs. CDH1 may mediate the association between CCBs and lifespan.</p><p><strong>Conclusions: </strong>BBs, CCBs and vasodilators may prolong lifespan, with potential sex differences for BBs and CCBs. The role of CCBs in lifespan is partly mediated by CDH1. Prioritizing the potential protein targets can provide new insights into healthy aging.</p>","PeriodicalId":11982,"journal":{"name":"European Heart Journal - Cardiovascular Pharmacotherapy","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Utilizing genetics and proteomics to assess the role of antihypertensive drugs in human longevity and the underlying pathways: a Mendelian randomization study.\",\"authors\":\"Bohan Fan, Jie V Zhao\",\"doi\":\"10.1093/ehjcvp/pvae038\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Antihypertensive drugs are known to lower cardiovascular mortality, but the role of different types of antihypertensive drugs in lifespan has not been clarified. Moreover, the underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>To minimize confounding, we used Mendelian randomization to assess the role of different antihypertensive drug classes in longevity and examined the pathways via proteins. Genetic variants associated with systolic blood pressure (SBP) corresponding to drug target genes were used as genetic instruments. The genetic associations with lifespan were obtained from a large genome-wide association study including 1 million European participants from UK Biobank and LifeGen. For significant antihypertensive drug classes, we performed sex-specific analysis, drug-target analysis and colocalization. To examine the mediation pathways, we assessed the associations of 2291 plasma proteins with lifespan, and examined the associations of drug classes with the proteins affecting lifespan.</p><p><strong>Results: </strong>After correcting for multiple testing, genetically proxied beta-blockers (BBs), calcium channel blockers (CCBs) and vasodilators were related to longer life years (BBs: 2.03, 95% CI 0.78 to 3.28 per 5-mmHg reduction in SBP, CCBs: 3.40, 95% CI 1.47 to 5.33, and vasodilators: 2.92, 95% CI 1.08 to 4.77). The beneficial effects of BBs and CCBs were more obvious in men. ADRB1, CACNA2D2, CACNB3, CPT1A, CPT2, and EDNRA genes were related to extended lifespan with CPT2 further supported by colocalization evidence. 86 proteins were related to lifespan, of which 4 proteins were affected by CCBs. CDH1 may mediate the association between CCBs and lifespan.</p><p><strong>Conclusions: </strong>BBs, CCBs and vasodilators may prolong lifespan, with potential sex differences for BBs and CCBs. The role of CCBs in lifespan is partly mediated by CDH1. 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引用次数: 0
摘要
背景：众所周知，降压药可降低心血管疾病死亡率，但不同类型的降压药在寿命中的作用尚未明确。此外，其潜在机制仍不清楚：为了最大限度地减少混杂因素，我们采用孟德尔随机法评估了不同类型的降压药对长寿的作用，并通过蛋白质研究了其作用途径。与药物靶基因相对应的收缩压（SBP）相关基因变异被用作遗传工具。与寿命相关的遗传变异来自一项大型全基因组关联研究，其中包括来自英国生物库和 LifeGen 的 100 万欧洲参与者。对于重要的抗高血压药物类别，我们进行了性别特异性分析、药物靶标分析和共定位分析。为了研究中介途径，我们评估了2291种血浆蛋白与寿命的关联，并研究了药物类别与影响寿命的蛋白的关联：经多重检验校正后，基因替代的β受体阻滞剂（BBs）、钙通道阻滞剂（CCBs）和血管扩张剂与延长寿命有关（BBs：SBP每降低5 mmHg，BBs的寿命为2.03，95% CI为0.78-3.28；CCBs：SBP每降低5 mmHg，CCBs的寿命为3.40，95% CI为1.28）：3.40，95% CI 1.47 至 5.33，血管扩张剂：2.92，95% CI 1.08 至 4.77）。BB类和CCB类药物对男性的益处更为明显。ADRB1、CACNA2D2、CACNB3、CPT1A、CPT2和EDNRA基因与延长寿命有关，其中CPT2得到了共定位证据的进一步支持。86种蛋白质与寿命有关，其中4种蛋白质受CCB影响。CDH1可能介导了CCBs与寿命之间的关联：结论：BBs、CCBs和血管扩张剂可延长寿命，其中BBs和CCBs可能存在性别差异。CCBs对寿命的作用部分由CDH1介导。对潜在的蛋白质靶点进行优先排序可为健康老龄化提供新的见解。
Utilizing genetics and proteomics to assess the role of antihypertensive drugs in human longevity and the underlying pathways: a Mendelian randomization study.
Background: Antihypertensive drugs are known to lower cardiovascular mortality, but the role of different types of antihypertensive drugs in lifespan has not been clarified. Moreover, the underlying mechanisms remain unclear.
Methods: To minimize confounding, we used Mendelian randomization to assess the role of different antihypertensive drug classes in longevity and examined the pathways via proteins. Genetic variants associated with systolic blood pressure (SBP) corresponding to drug target genes were used as genetic instruments. The genetic associations with lifespan were obtained from a large genome-wide association study including 1 million European participants from UK Biobank and LifeGen. For significant antihypertensive drug classes, we performed sex-specific analysis, drug-target analysis and colocalization. To examine the mediation pathways, we assessed the associations of 2291 plasma proteins with lifespan, and examined the associations of drug classes with the proteins affecting lifespan.
Results: After correcting for multiple testing, genetically proxied beta-blockers (BBs), calcium channel blockers (CCBs) and vasodilators were related to longer life years (BBs: 2.03, 95% CI 0.78 to 3.28 per 5-mmHg reduction in SBP, CCBs: 3.40, 95% CI 1.47 to 5.33, and vasodilators: 2.92, 95% CI 1.08 to 4.77). The beneficial effects of BBs and CCBs were more obvious in men. ADRB1, CACNA2D2, CACNB3, CPT1A, CPT2, and EDNRA genes were related to extended lifespan with CPT2 further supported by colocalization evidence. 86 proteins were related to lifespan, of which 4 proteins were affected by CCBs. CDH1 may mediate the association between CCBs and lifespan.
Conclusions: BBs, CCBs and vasodilators may prolong lifespan, with potential sex differences for BBs and CCBs. The role of CCBs in lifespan is partly mediated by CDH1. Prioritizing the potential protein targets can provide new insights into healthy aging.
期刊介绍：
The European Heart Journal - Cardiovascular Pharmacotherapy (EHJ-CVP) is an international, peer-reviewed journal published in English, specifically dedicated to clinical cardiovascular pharmacology. EHJ-CVP publishes original articles focusing on clinical research involving both new and established drugs and methods, along with meta-analyses and topical reviews. The journal's primary aim is to enhance the pharmacological treatment of patients with cardiovascular disease by interpreting and integrating new scientific developments in this field.
While the emphasis is on clinical topics, EHJ-CVP also considers basic research articles from fields such as physiology and molecular biology that contribute to the understanding of cardiovascular drug therapy. These may include articles related to new drug development and evaluation, the physiological and pharmacological basis of drug action, metabolism, drug interactions, and side effects.
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