Genetic insights into the role of cathepsins in cardiovascular diseases: a Mendelian randomization study.

Abstract

This study aimed to explore the causal relationships between cathepsins and cardiovascular diseases (CVDs) by Mendelian randomization (MR) analysis. 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: 14334 cases, 346860 controls) and a genome-wide association study (GWAS) (myocardial infarction: 20917 cases, 440906 controls; myocarditis: 633 cases, 427278 controls; chronic heart failure: 14262 cases, 471898 controls; angina pectoris: 30025 cases, 440906 controls; stable angina pectoris: 17894 cases, 325132 controls; unstable angina pectoris: 9481 cases, 446987 controls; pericarditis: 1795 cases, 453370 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). 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.