KEY GENETIC DETERMINANTS OF SEPSIS SUSCEPTIBILITY AND SEVERITY: A SYSTEMATIC MULTIDIMENSIONAL ANALYSIS

Background: Sepsis, a life-threatening condition driven by dysregulated immune responses, imposes a substantial global health burden. Despite advancements, its complex pathophysiology and urgent need for timely intervention underscore the necessity to identify novel genetic risk factors. This study aimed to systematically investigate causal genetic determinants of sepsis and its severe subtypes. Methods: Leveraging genome-wide association study data from the UK Biobank, two-sample Mendelian randomization analysis was performed on 72 candidate genes. Complementary methods included protein-protein interaction network mapping, heatmap visualization, Bayesian colocalization, regional association analysis, and transcriptomic sequencing. Results: A series of genes was identified to be causally associated with severe sepsis subtypes. The PSMA4 gene emerged as the most robust causal gene across all sepsis phenotypes (sepsis: β = 0.23, P = 4.07 × 10-36; sepsis in critical care: β = 0.22, P = 3.49 × 10-4; sepsis with 28-day death in critical care: β = 0.43, P = 5.94 × 10-19). Colocalization confirmed a shared causal variant between PSMA4 expression and sepsis risk (PP.H4.abf = 96.5%). In the transcriptomic data, we found that the expression of PSMA4 was significantly elevated in sepsis and septic shock patients (P = 0.003 for sepsis patients and P < 0.001 for septic shock patients, respectively). Conclusion: By employing a comprehensive multidimensional approach, we identified key genetic contributors to sepsis, with PSMA4 emerging as the most significant genetic risk factor underlying both susceptibility and disease severity. These findings highlighted PSMA4 as a therapeutic target, offering the potential for sepsis management.