G-Quadruplexes Formation in the PAI-1 Gene Modulates Sepsis-Induced Coagulopathy and Mortality Risk

BackgroundEarly detection of sepsis-induced coagulopathy (SIC) is of great clinical significance, as its closely correlates with disease progression in patients with sepsis. In the present study, we focused on mining the major coagulation factors that participate in the development and progression of SIC, and exploring the potential regulatory networks of these core factors.MethodMeta-analysis was performed to explore the association between SIC and mortality. eQTLs significantly associate with sepsis-related 28-day mortality and pQTLs were analyzed, to mine the significant sites or genes. Mendelian randomization (MR) was then applied to evaluate the role of coagulation factors in SIC and to explore their genetic regulation via DNA sequence analysis. Moreover, QGRS Mapper combined with ThT fluorescence assays were used to detect G-quadruplexes (G4s) structures within coagulation factor genes.ResultsSepsis patients with SIC exhibited higher sequential organ failure assessment (SOFA) scores and increased 28-day mortality compared to those without SIC. MR and clinical analyses demonstrated that PAI-1 serves as a major contributor to higher sepsis incidence and 28-day mortality. Notably, the PAI-1 rs1799762 genetic polymorphism alters this biological effect. Mechanistically, G4-forming capacity negatively correlates with PAI-1 expression. In particular, the 5G/5G genotype was associated with a higher G4-forming propensity in the PAI-1 gene, which in turn weakened gene transcription and lowered PAI-1 expression relative to other genotypes.ConclusionG4s formation in the PAI-1 gene modulates circulating PAI-1 levels and may serve as a novel prognostic marker and therapeutic target for sepsis severity assessment, particularly in patients with SIC.