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

TL;DR

This study identifies three plasma proteins linked to idiopathic pulmonary fibrosis, suggesting new potential targets for treatment.

Contribution

MASP1 and S100A11 are novel protective targets, while WFIKKN2 is a risk-increasing target for idiopathic pulmonary fibrosis.

Findings

MASP1 is associated with a decreased risk of idiopathic pulmonary fibrosis.

S100A11 levels are inversely related to idiopathic pulmonary fibrosis risk.

WFIKKN2 is linked to an increased risk of idiopathic pulmonary fibrosis.

Abstract

•Mendelian randomization reveals causal plasma proteins for idiopathic pulmonary fibrosis.•MASP1 and S100A11 are novel therapeutic targets lowering IPF risk.•WFIKKN2 is a potential therapeutic target that increases IPF risk.

Mendelian randomization reveals causal plasma proteins for idiopathic pulmonary fibrosis.

MASP1 and S100A11 are novel therapeutic targets lowering IPF risk.

WFIKKN2 is a potential therapeutic target that increases IPF risk.

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.

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