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Abstract

Background: Sepsis is a severe complication originating from an imbalanced host response to infection. Based on previous studies, the protein profile shows crucial participation in sepsis pathology. Observational studies on the relationship of circulating inflammatory proteins with sepsis susceptibility often confront difficulties related to reverse causality and confounding variables. The present study elucidated the potential causal effects of circulating inflammatory proteins on sepsis risk.

Methods: Here, a two-sample Mendelian Randomization (MR) analysis was conducted. The genetic instruments associated with inflammatory protein levels were derived using a genome-wide study of protein quantitative trait loci that involved 14,824 individuals based on the Olink Target platform. We then utilized summary data from the UK Biobank database, a large multicenter cohort study of >500,000 European individuals, to determine the associations of these proteins with sepsis and the related outcomes. The analysis included sepsis, sepsis (under 75 years of age), sepsis (28-day death) and sepsis (28-day death in critical care). Furthermore, the directionality of the results was confirmed using the Steiger test. Sensitivity analysis was carried out to examine the heterogeneity and pleiotropy of the results. Outliers were screened by the MR-PRESSO method.

Results: We identified causal relationships of sepsis with TNF-Related Apoptosis-Inducing Ligand (TRAIL) levels and vascular endothelial growth factor A levels. Sepsis (under 75 years) exhibited a causal relationship with TRAIL levels. Moreover, a causal relationship between sepsis (critical care) and TRAIL levels was also noted. Sepsis (28- day death) showed causal relationships with C-C motif chemokine 19 (CCL19), cystatin D and TRAIL levels. Finally, sepsis (28-day death in critical care) exhibited a causal relationship with the levels of CCL19 and CCL28.

 Conclusion: Our study provides evidence supporting the causal effects of few circulating inflammatory proteins on sepsis prognosis and susceptibility. These findings suggest that therapeutic interventions aimed at modulating these cytokine levels could have potential benefits for sepsis patients. Nonetheless, the validity and generalizability of our results should be confirmed through further research.