目的:本研究旨在通过孟德尔随机化(MR)分析探讨组织蛋白酶与心血管疾病(CVD)之间的因果关系。
结果:与九种组织蛋白酶类型(组织蛋白酶B,E,F,G,H,O,S,L2和Z)来自INTERVAL研究(3301名个体)。CVDs数据来自英国生物库(冠状动脉粥样硬化:14.334例,346.860对照)和全基因组关联研究(GWAS)(心肌梗塞:20.917例,440.906对照;心肌炎:633例,427.278对照;慢性心力衰竭:14.262例,471.898对照组;心绞痛:30.025例,440.906例对照;稳定型心绞痛:17.894例,325.132个对照;不稳定型心绞痛:9481例,446.987对照;心包炎:1795例,453.370控件)。反向方差加权(IVW),MR-Egger,采用加权中位数方法进行单变量MR(UVMR),反向MR,多变量MR(MVMR)分析以估计因果关系。UVMR分析表明,较高的组织蛋白酶E水平与冠状动脉粥样硬化风险增加[IVW:P=0.0051,比值比(OR)=1.0033,95%置信区间(CI)=1.0010-1.0056]和心肌梗死之间存在显着因果关系(IVW:P=0.0097,OR=1.0553,95%CI=1.0131-1.0993),而组织蛋白酶L2水平升高与心肌炎(IVW:P=0.0120,OR=0.6895,95%CI=0.5158-0.9216)和慢性心力衰竭(IVW:P=0.0134,OR=0.9316,95%CI=0.8807-0.9854)的风险降低有因果关系.反向MR分析显示心肌梗死增加了组织蛋白酶O的水平(IVW:P=0.0400,OR=1.0708,95%CI=1.0031-1.1431)。将九种组织蛋白酶一起处理的MVMR分析显示,组织蛋白酶E水平与冠状动脉粥样硬化风险之间存在正因果关系(IVW:P=0.0390,OR=1.0030,95%CI=1.0000-1.0060),组织蛋白酶L2水平对心肌炎(IVW:P=0.0030,OR=0.6610,95%CI=0.5031-0.8676)和慢性心力衰竭(IVW:P=0.0090,OR=0.9259,95%CI=0.8737-0.9812)的保护作用仍然存在,因为发现较高的组织蛋白酶O水平与心肌炎(IVW:P=0.0030,OR=1.6145,95%CI=1.1829-2.2034)和慢性心力衰竭(IVW:P=0.0300,OR=1.0779,95%CI=1.0070-1.1537)的风险增加有因果关系.
结论:该研究强调了组织蛋白酶E的因果关系,L2和CVD上的O,深入了解它们在心血管生物标志物和治疗靶点开发中的作用。需要进一步的研究才能在临床上应用这些遗传发现。
OBJECTIVE: This
study aimed to explore the causal relationships between
cathepsins and cardiovascular diseases (CVDs) by Mendelian randomization (MR) analysis.
RESULTS: Single nucleotide polymorphisms (SNPs) associated with nine cathepsin types (
cathepsins B, E, F, G, H, O, S, L2, and Z) were obtained from the INTERVAL
study (3301 individuals). CVDs data were acquired from the UK Biobank (coronary atherosclerosis: 14 334 cases, 346 860 controls) and a genome-wide association
study (GWAS) (myocardial infarction: 20 917 cases, 440 906 controls; myocarditis: 633 cases, 427 278 controls; chronic heart failure: 14 262 cases, 471 898 controls; angina pectoris: 30 025 cases, 440 906 controls; stable angina pectoris: 17 894 cases, 325 132 controls; unstable angina pectoris: 9481 cases, 446 987 controls; pericarditis: 1795 cases, 453 370 controls). Inverse variance weighted (IVW), MR-Egger, weighted median methods were adopted to conduct univariable MR (UVMR), reverse MR, multivariable MR (MVMR) analyses to estimate causality. The UVMR analyses demonstrated significant causal relationships between higher cathepsin E levels and increased risk of coronary atherosclerosis [IVW: P = 0.0051, odds ratio (OR) = 1.0033, 95% confidence interval (CI) = 1.0010-1.0056] and myocardial infarction (IVW: P = 0.0097, OR = 1.0553, 95% CI = 1.0131-1.0993), while elevated cathepsin L2 levels were causally related to reduced risk of myocarditis (IVW: P = 0.0120, OR = 0.6895, 95% CI = 0.5158-0.9216) and chronic heart failure (IVW: P = 0.0134, OR = 0.9316, 95% CI = 0.8807-0.9854). Reverse MR analyses revealed that myocardial infarction increased cathepsin O levels (IVW: P = 0.0400, OR = 1.0708, 95% CI = 1.0031-1.1431). MVMR analyses treating nine
cathepsins together revealed that the positive causality between cathepsin E levels and coronary atherosclerosis risk (IVW: P = 0.0390, OR = 1.0030, 95% CI = 1.0000-1.0060), and the protective effect of cathepsin L2 levels on myocarditis (IVW: P = 0.0030, OR = 0.6610, 95% CI = 0.5031-0.8676) and chronic heart failure (IVW: P = 0.0090, OR = 0.9259, 95% CI = 0.8737-0.9812) remained, as higher cathepsin O levels were found to be causally related to increased risks of myocarditis (IVW: P = 0.0030, OR = 1.6145, 95% CI = 1.1829-2.2034) and chronic heart failure (IVW: P = 0.0300, OR = 1.0779, 95% CI = 1.0070-1.1537).
CONCLUSIONS: The study highlights the causalities of cathepsin E, L2, and O on CVDs, offering insights into their roles in cardiovascular biomarkers and therapeutic targets development. Further research is required to apply these genetic findings clinically.