Identifying prioritization of potential targets for idiopathic pulmonary fibrosis: Proteome-wide Mendelian randomization and colocalization analyses.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive lung disorder characterized by limited therapeutic options. Thus, identifying new therapeutic targets for IPF is imperative. The authors employed 2 large-scale circulating proteomic and IPF GWAS (Ncase = 2189, Ncontrol = 407,609) to conduct proteome-wide Mendelian randomization meta-analysis. Subsequently, the authors utilized Summary Mendelian Randomization analysis and Bayesian colocalization to enhance the screening of proteins. Lastly, MR analysis of protein-protein level ratio, two-step MR method, enrichment analysis, Protein-Protein Interaction (PPI), and druggability assessment were applied to explore the potential mechanisms of candidate proteins. Through proteome-wide Mendelian randomization analysis and multiple validations, the authors identified 3 plasma proteins significantly associated with IPF. With strong evidence of colocalization and consistent support from SMR analysis, the gene-predicted MASP1 was correlated with decreased IPF risk (ORmeta = 0.46, 95% CImeta: 0.22‒0.99, Pmeta = 0.0478, PPH4 = 0.92). With suggestive colocalization support (PPH4 = 0.50), the levels of S100A11 were inversely related to IPF risk, with odds ratios of 0.53 (95% CIMR1 0.34-0.83, PMR1 = 0.0053). Conversely, the gene-predicted WFIKKN2 was associated with an increased risk of IPF (ORmeta = 1.31, 95% CImeta 1.15-1.48, Pmeta = 2.48E-05, PPH4 = 0.50). Their association was further supported by SMR analysis. Moreover, MR analysis of protein level ratio, mediator MR analysis, enrichment, and PPI network provided insights into the potential drug development based on the proteins. Our proteome-wide Mendelian Randomization analysis highlighted MASP1, S100A11, and WFIKKN2 as potential targets for further clinical investigation in IPF. The specific mechanisms by which these proteins influence IPF pathogenesis require further elucidation through continued research.