miR-eQTLs Reveal Causal Association and Regulatory Mechanism of miRNAs and Sepsis.

BACKGROUND

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and its pathogenesis remains unclear. MicroRNAs (miRNAs) play crucial roles in regulating gene expression and have been implicated in various diseases, including sepsis.

METHODS

This study investigated the causal associations of miR-expression quantitative trait loci (miR-eQTL) with sepsis through Mendelian randomization (MR) analysis. We analyzed 2,083 miR-eQTLs using the inverse variance weighting method and validated the results with sensitivity analyses. We obtained messenger RNA (mRNA) targets of these miRNAs and performed pathway enrichment analysis and protein-protein interaction (PPI) network construction. Additionally, using 11 topological algorithms, we analyzed the PPI network to determine the core genes of target genes.

RESULTS

The findings revealed that 74 miRNAs were causally associated with sepsis, with 33 acting as protective factors and 41 as risk factors. A stringent filtering approach identified nine miRNAs, including miR-6775-3p, miR-1296-3p, miR-4317, miR-3144-3p, miR-4798-3p, miR-581, miR-3,185, miR-221-3p, and miR-340-5p. Sensitivity analyses confirmed the robustness of these associations, with no significant heterogeneity, pleiotropy, or directionality issues. Through pathway enrichment analysis and PPI network construction, we identified core genes. The pathway enrichment analysis highlighted significant enrichments in various biological processes and pathways, including the FoxO signaling pathway, Wnt signaling pathway, and Ras signaling pathway. Using 11 topological algorithms, we screened out 25 PPI core genes. The miRNA-mRNA interaction network further elucidated the regulatory roles of these miRNAs.

CONCLUSION

This study offers new insights into miRNA-mediated mechanisms in sepsis and identifies potential therapeutic targets for this complex syndrome, although additional validation is necessary.