Genetic Evidence Reveals a Causal Association Between Plasma Phosphatidylcholine Levels and Sepsis Associated Mortality, With Immune Cells Mediating This Association

Abstract Background Sepsis is a critical and life-threatening clinical syndrome. Abnormal plasma lipid levels are associated with disease progression. However, causal links remain uncertain due to limitations of observational studies. Methods This study conducted a comprehensive two-sample Mendelian randomization (MR) analysis utilizing publicly available pooled genome-wide association study (GWAS) data on 179 plasma phospholipid subtypes, 731 immune cell phenotypes, and genetic data related to sepsis-related mortality outcomes. The causal associations between plasma lipids, immune cell phenotypes, and the risk of sepsis-related death were investigated. Results MR results demonstrated significant causal associations between five subtypes of phosphatidylcholine (PC) and one sphingomyelin (SM) and the clinical outcome of 28-day mortality in sepsis patients. Notably, PC(16:0_18:2), PC(18:0_18:1), PC(18:0_20:4), PC(O-16:1_16:0), and SM(d34:0) demonstrated a protective effect in reducing the risk of 28-day mortality( P < 0.05). Conversely, PC(16:1_20:4) was associated with an increased risk of 28-day mortality in sepsis patients( P < 0.05). Comprehensive sensitivity analyses confirmed the robustness of these results. The inverse Mendelian randomization analysis did not reveal a significant causal effect of sepsis on the aforementioned lipid profile. Mediation analysis identified two key immune cell-mediated factors, including circulating CD39 on CD39 + CD8br cells and CX3CR1 on CD14+ CD16+ monocytes, as mediators of the reduced risk of sepsis-associated mortality due to PC(O-16:1_16:0), with mediation proportions of 17.4% and 13.6%, respectively. Conclusions Our study supports a causal relationship between plasma lipid metabolism disorders and sepsis-associated mortality and provides new insights into the critical role of immune cell alterations induced by lipid metabolism disorders in sepsis progression.