Identifying Causal Inflammatory Factors With Gene Mediators and Potential Drugs for Bronchiectasis

Abstract

Background

Bronchiectasis is a chronic respiratory disease characterized by irreversible dilation of the bronchi. Despite advancements in diagnostic techniques and therapeutic strategies, the underlying etiological factors driving bronchiectasis pathogenesis remain unclear. The purpose of this study was to explore the potential causal relationship between inflammatory factors and bronchiectasis to better understand the disease's molecular mechanisms and identify possible therapeutic targets.

Methods

Genome-wide data were utilized to conduct two-sample Mendelian randomization (MR) focusing on the causal relationships between 41 inflammatory factors and bronchiectasis. The reliability of the results was validated by sensitivity tests. Summary data-based MR, coloc, and intermediary MR were utilized to determine latent upstream genes and estimate indirect effects. Molecular docking was applied to identify existing effective drugs.

Results

Four inflammatory factors with potential causal effects on bronchiectasis were identified: macrophage migration inhibitory factor, interleukin-4, interferon-gamma (IFN-γ), and basic fibroblast growth factor (bFGF). Additional sensitivity tests tended to support the directional consistency of the IFN-γ and bFGF estimates. RP11-589P10.5 reduced the risk of bronchiectasis mediated by the IFN-γ concentration. Metronidazole, ibuprofen, methotrexate, pioglitazone, and ciprofloxacin were identified as effective therapeutic drugs, whereas simvastatin was predicted to be harmful. Ciprofloxacin and lansoprazole were also identified as potentially therapeutic and harmful drugs with the strongest binding activities, respectively.

Conclusions

This study provides strong evidence for the causal effects of macrophage migration inhibitory factor, interleukin-4, IFN-γ and bFGF in bronchiectasis, especially the latter two inflammatory factors. RP11-589P10.5 latently decreased the risk of bronchiectasis mediated by IFN-γ. Methotrexate, lansoprazole, and pioglitazone were predicted to have potential therapeutic values.