No Causal Relationship Between Coagulation Factors and Sepsis-Related Risks: A Mendelian Randomization Study

Abstract Background Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Among the critical hallmarks of sepsis progression is the abnormal activation of coagulation, particularly the onset of disseminated intravascular coagulation, which often indicates a higher risk of mortality. However, due to the complexity of the coagulation system and the lack of prospective sepsis cohorts, understanding the relationship between coagulation factors and sepsis-related risk remains limited. Therefore, this study aims to investigate the association between coagulation factor levels and related protein expressions with the risk of sepsis incidence, ICU admission, and 28-day mortality using publicly available GWAS summary statistics through MR analysis. Methods To explore the causal relationship between coagulation factors and sepsis-related risks, we employed a two-sample MR analysis framework. After rigorous quality control, we extracted 99 SNPs influencing the plasma levels of 16 coagulation factors from GWAS. Cis-eQTLs regulating sepsis-related coagulation genes were extracted from the eQTLgen database as instrumental variables. We then utilized sepsis GWAS data from independent European ancestry cohorts: UK Biobank and FinnGen as outcome data for MR analysis. We calculated MR estimates using various methods and conducted sensitivity analyses to ensure the robustness of the analysis. Results The causal effect sizes between genetically predicted levels of coagulation factors and the risk of sepsis incidence, ICU admission, and 28-day mortality did not reach statistical significance. The expression of the TMEM173 gene showed a positive effect on the risk of ICU admission for sepsis (IVW: beta = 0.362, P = 0.0264; Weighted Median: beta = 0.386, P = 0.0123). Conclusions Our MR study does not support a presumed causal effect between coagulation factor levels and the risk of sepsis incidence, ICU admission, and 28-day mortality in European populations.