Exploring the Causal Relationship Between Circulating miRNAs and Sepsis Through Mendelian Randomization Analysis.

Area of Science:

• Genetics
• Molecular Biology
• Epidemiology

Background:

• MicroRNAs (miRNAs) are implicated in sepsis pathophysiology, with altered expression observed in patients.
• Circulating miRNAs in peripheral blood offer potential biomarkers for sepsis.

Purpose of the Study:

• To investigate the causal relationships between circulating miRNAs and sepsis risk.
• To identify specific miRNAs that may protect against or increase susceptibility to sepsis.

Main Methods:

• Employed Mendelian Randomization (MR) analysis using miRNA expression quantitative trait loci (eQTL) and sepsis genome-wide association study (GWAS) data.
• Utilized Inverse Variance Weighted (IVW) and MR-Egger regression methods to assess causal associations.
• Performed target identification and pathway enrichment analyses for significant miRNAs.

Main Results:

• Identified three miRNAs (hsa-miR-125a-5p, hsa-miR-494-3p, hsa-miR-885-5p) associated with reduced sepsis risk (protective effect).
• Identified three miRNAs (hsa-miR-196b-5p, hsa-miR-27b-3p, hsa-miR-598-3p) associated with increased sepsis risk.
• Validated the association of hsa-miR-27b-3p with increased sepsis risk in an independent cohort.
• Found miRNA targets enriched in pathways related to bacterial infection, apoptosis, and FoxO signaling.

Conclusions:

• Established causal links between specific circulating miRNAs and sepsis risk using MR.
• Highlighted potential protective and detrimental roles of circulating miRNAs in sepsis.
• Suggests circulating miRNAs as novel targets for sepsis prevention, diagnosis, and treatment strategies.