Association of 41 circulating inflammatory factors, C-reactive protein, and procalcitonin with sepsis risk and 28-day mortality: A bidirectional Mendelian randomization and mediation analysis.

BACKGROUND

The precise causal relationship between circulating inflammatory factors and sepsis has not yet been fully elucidated.

OBJECTIVES

To identify biomarkers that enable earlier and more accurate diagnosis of sepsis.

MATERIAL AND

METHODS

The causal relationships between 41 circulating inflammatory factors, C-reactive protein (CRP), and procalcitonin (PCT) with sepsis and 28-day sepsis-related mortality were evaluated using two-sample bidirectional Mendelian randomization (MR) analyses.

RESULTS

This study revealed negative causal associations between genetically predicted circulating inflammatory factors-interleukin-6 (IL-6) (odds ratio [OR] = 0.923; 95% confidence interval [CI], 0.854-0.998; p = 0.044), RANTES (OR = 0.926; 95% CI, 0.862-0.994; p = 0.033), and macrophage inflammatory protein-1β (MIP1β) (OR = 0.957; 95% CI, 0.919-0.996; p = 0.032) - and the risk of sepsis. Furthermore, positive causal relationships were observed between CRP and sepsis (OR = 1.140; 95% CI: 1.055-1.232; p = 0.001), as well as between CRP and 28-day sepsis-related mortality (OR = 1.241; 95% CI: 1.034-1.489; p = 0.020). Platelet-derived growth factor-BB (PDGF-BB) levels were also elevated in sepsis (OR = 1.136; 95% CI: 1.003-1.286; p = 0.044). Mediation analysis indicated that CRP mediated the effects of IL-6 and RANTES on sepsis, accounting for 25.87% (OR = 0.980; 95% CI: 0.961-0.998) and 2.04% (OR = 1.002; 95% CI: 0.991-1.012) of the total effect, respectively. The robustness of these associations was confirmed through leave-one-out sensitivity analysis and funnel plots.

CONCLUSIONS

This study enhances our understanding of the mechanisms underlying sepsis and its associated mortality, and underscores the therapeutic potential of targeting inflammatory factors in its management.