Causality between cathepsins and idiopathic pulmonary fibrosis: a Mendelian randomization study

Abstract Background The pathogenesis of idiopathic pulmonary fibrosis (IPF) is complex and difficult to diagnose and treat clinically. Cathepsins are involved in various physiological and pathological processes, and observational studies have shown an association between cathepsins and IPF. However, the causal relationship between them remains uncertain. Our aim was to assess the causal relationship between various cathepsins and IPF. Methods Protein quantitative trait loci (pQTL) data for cathepsins were obtained from INTERVAL studies, and summary statistics for IPF genome-wide association studies (GWAS) were obtained from the FinnGen R10 study. Univariable Mendelian randomization (UVMR), multivariable Mendelian randomization (MVMR), summary data-based Mendelian randomization (SMR) and Bayesian colocalization analysis were conducted in this study. Results UVMR analysis indicated that elevated cathepsin H levels reduced the overall risk of IPF (OR = 0.885,95%CI = 0.827 ~ 0.947, P = 3.86×10 − 4). MVMR showed that the effect of cathepsin H on IPF was still present after adjusting the interaction of cathepsins (OR = 0.895,95%CI = 0.834 ~ 0.961, P = 0.002). In addition, SMR analysis also suggested a causal association between cathepsin H and IPF (OR = 0.800,95%CI = 0.699 ~ 0.916, P = 0.001). Finally, we validated the results using the UK Biobank Pharma Proteomics Project (UKB-PPP) dataset (OR = 0.897,95%CI = 0.836 ~ 0.963, P = 0.003). Conclusions This study suggests that cathepsin H has a protective effect on IPF and may serve as a potential therapeutic target for IPF, providing inspiration and guidance for the diagnosis and treatment of IPF.