INFLAMMATORY PROTEIN SIGNATURES OF SEPSIS RISK AND MORTALITY: A MENDELIAN RANDOMIZATION STUDY.

Abstract: Objective: Sepsis represents a leading cause of global mortality, defined by a dysregulated inflammatory response. This study aims to investigate the potential causal associations between circulating inflammatory proteins and sepsis risk using a two-sample Mendelian randomization (MR) approach. Methods: Publicly available summary statistics from genomewide association studies (GWAS) were used in this study. Genetic instruments for circulating inflammatory protein were derived from a GWAS meta-analysis of 11 cohorts encompassing 14,824 European participants. The relationship between genetically predicted protein levels and sepsis-related outcomes was evaluated using aggregated data from the UK Biobank-a multicenter prospective cohort study comprising over 500,000 European participants. Analyses were stratified by age, 28-day mortality, and ICU admission. Multiple MR methods, including inverse-variance weighted (IVW), MR-Egger, and weighted median, were applied to ensure the robustness of our findings. Results: The MR analysis identified significant causal associations between inflammatory proteins and sepsis outcomes. Genetically predicted elevated levels of β-NGF are associated with a reduced risk of sepsis (odds ratio [OR] 0.77, 95% confidence interval [CI] = 0.60-0.99; P = 0.039). Among sepsis patients aged below 75 years, the risk was reduced by 30% (OR, 0.70; 95% CI = 0.52-0.93; P = 0.013). Genetically predicted increases in TRAIL (OR, 1.11; 95% CI = 1.02-1.20; P = 0.020) and VEGF-A (OR, 1.18; 95% CI = 1.02-1.37; P = 0.031) were positively associated with sepsis incidence, while genetically predicted levels of CST5 (OR, 0.81; 95% CI = 0.69-0.94; P = 0.006) and MCP-1 (OR, 0.64; 95% CI = 0.45-0.92; P = 0.015) were inversely associated with sepsis-induced mortality. Conclusion: This study provides evidence from a Mendelian randomization framework supporting the causal role for specific circulating inflammatory proteins (e.g., β-NGF, VEGF-A, and TRAIL) in influencing sepsis risk and mortality. These findings underscore the potential for therapeutic interventions targeting these proteins to mitigate sepsis risk and improve patient outcomes, along with further investigation into the underlying mechanisms and clinical implications.