Abstract
Research suggests that cathepsins, due to their extensive mechanisms of action, may play a crucial role in cardiomyopathies. However, further studies are necessary to establish causality. This study aims to investigate the causal relationship between cathepsins and various types of cardiomyopathies. This study investigated causal associations between 9 cathepsins and cardiomyopathies, including their subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, and restrictive cardiomyopathy, using pooled data from genome-wide association studies. The analyses employed inverse variance weighted (IVW), Mendelian randomization (MR)-Egger, and weighted median methods for univariable MR, reverse MR, and multivariable MR to estimate causality. For sensitivity analyses, we applied Cochran Q test, MR-PRESSO, MR-Egger intercept test, and the leave-one-out method to ensure the robustness and reliability of our findings. Univariable MR analyses indicated that elevated levels of cathepsin E were associated with an increased risk of overall cardiomyopathy (IVW: P = .045, odds ratio [OR] = 1.078, 95% confidence interval [CI] = 1.002-1.160). Conversely, higher levels of cathepsin B were linked to a reduced risk of HCM (IVW: P = .037, OR = 0.856, 95% CI = 0.740-0.990), and higher cathepsin O levels were causally related to a reduced risk of HCM (IVW: P = .04, OR = 0.810, 95% CI = 0.662-0.991). Reverse MR analyses indicated that a higher risk of HCM was causally related to increased levels of cathepsin E (IVW: P = .038, OR = 1.024, 95% CI = 1.001-1.047). Multivariable MR analyses showed that increased cathepsin E levels still correlated with increased overall cardiomyopathy, even after the addition of other types of cathepsins (IVW: P = .0165, OR = 1.005, 95% CI = 1.0176-1.1901), while cathepsin O levels remained causally related to a reduced risk of HCM (IVW: P = .0053, OR = 0.7183, 95% CI = 0.5692-0.9065). Cathepsin L2 was also found to be associated with an increased risk of restrictive cardiomyopathy (IVW: P = .0374, OR = 2.1337, 95% CI = 1.0450-4.3565). This study demonstrates the causal relationship between cathepsins E, B, L2, O and the development of cardiomyopathy. The findings may be crucial for early diagnosis, prognosis prediction, molecular classification, and identifying potential therapeutic targets for cardiomyopathy.