Elucidating the Causal Relationships between Circulating Inflammatory Proteins and Sepsis Outcomes: A Mendelian Randomization Approach

Introduction: Sepsis has been associated with numerous circulating proteins, yet traditional studies have struggled to clarify whether these protein biomarkers directly contribute to disease progression. Methods: Our study aimed to explore the causal effects of 91 circulating inflammation- related proteins (CIPs) on sepsis using a two-sample Mendelian randomization (MR) approach. We employed the inverse variance weighted (IVW) method as our primary analytical tool, supplemented by additional methods, such as weighted median, weighted mode, simple median, MR-Egger, and MR-PRESSO analyses. Comprehensive sensitivity analyses were carried out to rigorously assess the robustness of our findings, which substantiated the lack of significant heterogeneity and ruled out the presence of horizontal pleiotropy. Results: Our study identified 2 CIPs with statistically significant causal effects on sepsis: fractalkine (OR=2.383, 95% CI=1.380-4.113, p=0.002) and IL-12 (OR=0.780, 95% CI=0.610-0.997, p=0.047). These results suggested that fractalkine and IL-12 might play a contributory role in the risk of sepsis. The implications of our findings are substantial, highlighting fractalkine and IL-12 as potential therapeutic targets for sepsis prevention and treatment. The reliability of our results was further reinforced by sensitivity analyses, which demonstrated no evidence of heterogeneity or pleiotropy. Conclusion: This study offered new insights into sepsis pathophysiology and identified potential therapeutic targets. Further studies are required to validate these findings and elucidate the precise roles of these proteins.