Exploring Causal Cytokines and Potential Regulatory Genes in Bronchiectasis: Findings from Mendelian randomization

Abstract

Abstract Background Bronchiectasis is a chronic respiratory disease characterized by irreversible dilation of the bronchi, which leads to impaired mucociliary clearance, recurrent infections, and inflammatory responses. Despite advancements in diagnostic techniques and therapeutic strategies, the underlying etiological factors driving bronchiectasis pathogenesis remain incompletely elucidated. Methods Genome-wide data were utilized to conduct two-sample Mendelian randomization focusing on the causality from 41 inflammatory factors on bronchiectasis. Sensitivity tests were carried out to validate the reliability. SMR, coloc, and intermediary Mendelian randomization were utilized to determine latent upstream genes and estimate indirect effects. Results Four inflammatory factors’ potential causal effects on bronchiectasis were identified: MMIF (0.85 (0.74, 0.98) 0.029), IL-4 (1.32 (1.09, 1.55) 0.019), IFN-γ (1.28 (1.02, 1.60) 0.032), and FGF-Basic (1.28 (1.03, 1.59) 0.025) (FinnGen R9, IVW, reported as OR (95% CI) P). Sensitivity tests supported the direction consistency of IFN-γ and FGF-Basic’s estimates instead of MMIF and IL-4. RP11-589P10.5 was found to reduce the risk of bronchiectasis, mediated by the IFN-γ concentration (OR = 0.96, proportion = 36.52%). Conclusions Our study has identified strong evidence for potential positive causalities from IFN-γ and FGF-Basic. RP11-589P10.5 was found to latently decrease the risk of bronchiectasis, which is mediated by IFN-γ. At the genetic level, we anticipate that the cytokines and the gene can be taken into account in predictive models for bronchiectasis and even as indicators of the severity of the disease, providing new directions for future population research and basic experiments related to bronchiectasis.