Causal association between cathepsins and asthma: a Mendelian randomization study

Asthma, a chronic respiratory disease affecting millions worldwide, poses a significant public health burden. Cathepsins, a group of proteolytic enzymes, have recently been implicated in asthma pathophysiology, though their exact causal role remains unclear. To address this gap, we conducted univariate and multivariate Mendelian randomization (MR) analyses using data from the INTERVAL study (3301 European ancestry participants) and FinnGen consortium (46,684 asthma cases and 219,734 controls). Our analysis employed inverse variance weighting (IVW), median weighting, and MR-Egger regression to ensure robustness and explore causality from multiple perspectives. Sensitivity analyses were performed to assess heterogeneity and pleiotropy.Results indicated a significant association between elevated cathepsin L2 levels and increased asthma risk (OR  1.058, 95% CI 1.016-1.101, P = 0.006), suggesting a potential role of cathepsin L2 in asthma pathogenesis. No significant effect of asthma status on cathepsin L2 levels was observed (P = 0.550), ruling out reverse causality. Multivariable MR further confirmed the independent association of cathepsin L2 with asthma risk. Sensitivity analyses supported these findings with no evidence of significant pleiotropy.This study is the first to apply Mendelian randomization to explore the causal relationship between cathepsins and asthma, highlighting cathepsin L2 as a key player in asthma pathophysiology. These findings offer novel insights into asthma mechanisms and suggest cathepsin L2 as a potential therapeutic target warranting further investigation.