Related Experiment Video
Updated: May 12, 2026
Evaluation of Vascular Control Mechanisms Utilizing Video Microscopy of Isolated Resistance Arteries of Rats
Published on: December 5, 2017
Genetic insights into the role of cathepsins in cardiovascular diseases: a Mendelian randomization study
Ruiqi Zeng1,2, Zhiyi Zhou1,3, Wanzhe Liao1,2
1Guangzhou Medical University, Guangzhou, 511436, China.
Insights
This Mendelian randomization study found that cathepsin E increases cardiovascular disease risk, while cathepsin L2 offers protection against myocarditis and heart failure. Cathepsin O is linked to increased myocarditis and heart failure risks.
Area of Science:
- Genetics and Cardiovascular Medicine
- Biomarker Discovery
- Causal Inference
Background:
- Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide.
- The role of cathepsins, a family of proteases, in CVD pathogenesis is not fully understood.
- Genetic association studies have suggested links between cathepsins and cardiovascular health.
Purpose of the Study:
- To investigate the causal relationships between nine cathepsin types and various cardiovascular diseases using Mendelian randomization (MR).
- To identify potential cathepsin-related biomarkers and therapeutic targets for CVDs.
Main Methods:
- Utilized Mendelian randomization (MR) analysis with single nucleotide polymorphisms (SNPs) from the INTERVAL study for cathepsin levels.
- Employed large-scale cardiovascular disease datasets from UK Biobank and GWAS for coronary atherosclerosis, myocardial infarction, myocarditis, and heart failure.
- Applied univariable MR (UVMR), reverse MR, and multivariable MR (MVMR) analyses, including Inverse Variance Weighted (IVW) and MR-Egger methods.
Main Results:
- Elevated cathepsin E levels showed a causal link to increased risk of coronary atherosclerosis and myocardial infarction.
- Higher cathepsin L2 levels were causally associated with a reduced risk of myocarditis and chronic heart failure.
- Reverse MR indicated that myocardial infarction may increase cathepsin O levels.
- MVMR confirmed the causal effects of cathepsin E on coronary atherosclerosis, cathepsin L2 on myocarditis and heart failure, and identified a causal role for cathepsin O in myocarditis and heart failure.
Conclusions:
- Cathepsin E, L2, and O play significant causal roles in the development of specific cardiovascular diseases.
- These findings provide valuable insights into the mechanisms underlying CVDs and highlight potential therapeutic targets.
- Further clinical research is warranted to translate these genetic findings into practical applications for cardiovascular health.
Aims:
This study aimed to explore the causal relationships between cathepsins and cardiovascular diseases (CVDs) by Mendelian randomization (MR) analysis.
Methods And 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.
Related Concept Videos
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
01:29Pharmacogenomics: Identification of New Drug Targets
01:30Coronary Artery Disease I: Introduction