Association between cathepsins and cardiomyopathy: A Mendelian randomization study

Area of Science:

• Biochemistry
• Genetics
• Cardiology

Background:

• Cathepsins are enzymes with diverse functions, potentially implicated in cardiomyopathies.
• Establishing a causal link between cathepsins and cardiomyopathies requires further investigation.

Purpose of the Study:

• To investigate the causal associations between nine cathepsins and cardiomyopathies, including hypertrophic, dilated, and restrictive subtypes.
• To explore the role of cathepsins in the pathogenesis of different cardiomyopathy types using Mendelian randomization.

Main Methods:

• Employed Mendelian randomization (MR) analyses, including inverse variance weighted (IVW), MR-Egger, and weighted median methods.
• Utilized pooled genome-wide association study data for nine cathepsins and cardiomyopathy subtypes.
• Performed sensitivity analyses using Cochran Q test, MR-PRESSO, MR-Egger intercept, and leave-one-out methods to ensure result robustness.

Main Results:

• Elevated cathepsin E levels were associated with increased overall cardiomyopathy risk (P=.045, OR=1.078).
• Higher cathepsin B (P=.037, OR=0.856) and cathepsin O (P=.04, OR=0.810) levels were linked to reduced hypertrophic cardiomyopathy (HCM) risk.
• Cathepsin L2 showed an association with increased restrictive cardiomyopathy risk (P=.0374, OR=2.1337).
• Reverse MR indicated a causal link between higher HCM risk and increased cathepsin E levels (P=.038, OR=1.024).
• Multivariable MR confirmed cathepsin E's association with overall cardiomyopathy and cathepsin O's association with reduced HCM risk.

Conclusions:

• Demonstrates a causal relationship between cathepsins E, B, L2, and O and cardiomyopathy development.
• Findings suggest cathepsins as potential biomarkers for early diagnosis and prognosis in cardiomyopathies.
• Identifies cathepsins as potential therapeutic targets for managing cardiomyopathy.