Novel treatment strategies for cardiovascular and pulmonary diseases: Insights from cathepsin-related Mendelian randomization and Bayesian colocalization

Cardiopulmonary diseases, encompassing cardiovascular and pulmonary disorders, represent a major global health burden, with cathepsins (CTSs) - proteases involved in extracellular matrix degradation and inflammation - have established causal links to cardiovascular disease, but their roles in lung pathologies like idiopathic pulmonary fibrosis (IPF) remain uncertain. We performed bidirectional Mendelian randomization (MR) to assess causal relationships between plasma levels of 11 CTSs and 10 common cardiopulmonary diseases. Heterogeneity and horizontal pleiotropy were evaluated using Cochran's Q test and MR-Egger intercept, respectively. Protein-protein interaction networks were analyzed via STRING, and Bayesian colocalization tested for shared causal variants underlying CTS interactions and CTS-disease associations. Bidirectional MR identified CTSH as a protective factor for IPF (inverse variance weighted odds ratio: 0.885, 95% confidence interval: 0.827-0.947, P = 3.86 × 10⁻⁴), with no reverse causality detected; STRING analysis revealed CTSH interactions with CTSL and CTSD; Bayesian colocalization yielded posterior probabilities (PPH4) of 0.0336 (CTSH-CTSD), 0.0477 (CTSH-CTSL), and 0.7955 (CTSH-IPF). Nominal causal associations were observed between CTSE and cardiovascular diseases, and between myocardial infarction and CTSL/CTSO/CTSZ, though these require further validation. Our findings genetically support CTSH as a protective factor against IPF, highlighting its potential as a therapeutic target. Further studies are needed to validate additional CTS-disease associations.