Abstract：
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.
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.
摘要：
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。
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。
