Causal Relationships Between Inflammatory Cytokines and Sepsis: A Mendelian Randomization Study.

Abstract

Objective: The complex interplay between inflammatory cytokines and sepsis is not well understood. This study employs Mendelian Randomization (MR) to investigate the causal relationships between various inflammatory cytokines and sepsis, aiming to elucidate the underlying mechanisms and potential therapeutic targets.

Methods: This study employed a bidirectional MR approach to investigate the causal effects of inflammatory cytokines on sepsis and vice versa. Genetic variants from genome-wide association studies (GWAS) were used as instrumental variables (IVs). Key MR methods included Inverse Variance Weighted (IVW), MR-Egger, and Weighted Median. SNPs were filtered using a p-value threshold of <5e-08, with linkage disequilibrium exclusions (r²<0.001). We analyzed 41 inflammatory cytokines, utilizing leave-one-out analysis and MR-PRESSO to address pleiotropy.

Results: The MR analysis revealed significant causal relationships between specific cytokines and sepsis. CTACK (OR=1.102, P=0.031), MIF (OR=1.071, P=0.036), and TRAIL (OR=1.053, P=0.036) were identified as risk factors, while MIP1-β (OR=0.933, P=0.039) and TGF-α (OR=0.957, P=0.029) emerged as protective factors. Additionally, sepsis increased the risk for IL-2 (OR=1.455, P<0.01), IL-6 (OR=1.151, P= 0.012), and MCSF (OR=1.272, P=0.028), while showing a protective effect on NGF-β (OR=0.78, P=0.012) and SCF (OR=0.86, P=0.02).

Conclusion: This study reveals novel causal relationships between specific inflammatory cytokines and sepsis, suggesting that CTACK, MIF, and TRAIL are risk factors, while MIP1-β and TGF-α are protective. Additionally, sepsis influences various cytokines, indicating complex bi-directional interactions. These findings provide valuable insights for developing targeted therapeutic strategies to manage sepsis and inflammatory responses.