Three immune cell types are associated with mediating the relationship between and at rates of 6.5%, 12.8%, and 3.9%.
A total of 33 overlapping genes were identified between COPD and sepsis.
AIM2 and RNF125 are highlighted as key diagnostic genes.
Dysregulation was observed in monocyte, macrophage, plasma, and dendritic cell populations.
Nine key co-regulators were identified through regulatory network analysis.
Ten potential drug targets were discovered, with seven validated by molecular docking.
Simplified
BACKGROUND: Evidence suggests a bidirectional association between (COPD) and , but the underlying mechanisms remain unclear. This study aimed to explore shared diagnostic genes, potential mechanisms, and the role of immune cells in the COPD-sepsis relationship using Mendelian randomization (MR) and bioinformatics approaches, while also identifying potential therapeutic drugs.
METHODS: Two-sample MR analysis was performed using genome-wide association data to assess genetically predicted COPD and sepsis. Immune cell-mediated effects were quantified using a two-way two-sample MR analysis. Differential expression gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) were used to identify common genes. Functional enrichment analyses were conducted to explore the biological roles of these genes. LASSO and SVM-RFE algorithms identified shared diagnostic genes, which were evaluated using receiver operating characteristic (ROC) curves. Immune cell infiltration was analyzed with CIBERSORT, while transcription factor (TF) and miRNA networks were constructed using NetworkAnalyst. Drug predictions were made using DSigDB, and molecular docking validated potential drugs.
RESULTS: Three immune cell types were identified as mediators between COPD and sepsis, with genetically predicted effects mediated by these cells at rates of 6.5%, 12.8%, and 3.9%. A total of 33 overlapping genes were identified, and AIM2 and RNF125 were highlighted as key diagnostic genes. Immune infiltration analysis revealed dysregulated monocyte, macrophage, plasma, and dendritic cells. Regulatory network analysis identified nine key co-regulators. Ten potential drug targets were identified, with seven validated via molecular docking.
CONCLUSION: AIM2 and RNF125 may serve as diagnostic biomarkers, and identified immune cell subsets could mediate the COPD-sepsis connection, offering insights into potential therapeutic targets.
Key numbers
6.5%
Increase in Risk
Proportion of risk increase mediated by CD33bright HLA DR+ CD14- immune cells.
12.8%
Increase in Risk
Proportion of risk increase mediated by BAFF-R on IgD- CD38bright immune cells.
3.9%
Increase in Risk
Proportion of risk increase mediated by CD45 on CD33- HLA DR+ immune cells.
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Xinyi Li and Yuyang Xiao are co-first authors for this study. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
