Causal Networks among Lipidomes, Immunophenotypes, Sepsis, and related poor prognosis: Novel Insights from Mendelian Randomization

This investigation seeks to illuminate the intricate causal network linking lipidomes, immunocyte phenotypes, sepsis occurrence, and the ensuing 28-day mortality. By deploying Mendelian randomization, we systematically scrutinized the causal roles of 179 lipid species and 731 immune cell phenotypes in sepsis incidence and related mortality risk using the largest genome-wide association datasets accessible. Our analyses unveiled subtle causal connections implicating 9 specific lipid species and 37 immune traits in sepsis etiology, alongside 15 lipids and 47 immune profiles demonstrating suggestive causal impacts on 28-day mortality, all devoid of heterogeneity, horizontal pleiotropy, or reverse causality signals. Following rigorous Bonferroni correction, triacylglycerol (50:3) (Odds Ratio [OR] = 0.90, 95% Confidence Interval [CI], 0.86-0.96, P = 7.4E-05) and CD66b++ myeloid cell (OR = 0.94, 95% CI, 0.92-0.97, P = 2.5E-04) retained statistical significance in association with the occurrence of sepsis. Moreover, the heightened CD45 on CD14+ monocyte (OR= 1.22, 95% CI: 1.10-1.34, P= 8.3E-05) and reduced BAFF-R on IgD- CD38+ B cell (OR= 0.79, 95% CI: 0.70-0.89, P= 1.6E-04) persisted as significant predictors of 28-day mortality in sepsis. Of particular note, we uncovered that activated and resting CD4 regulatory T cell absolute count mediated 5.2% of the effect of triacylglycerol (50:3) on sepsis onset risk, and BAFF-R expression on IgD- CD38+ B cells mediated 14.9% of the impact of phosphatidylcholine (16:0_22:5) on sepsis-linked 28-day mortality risk. These genetic insights illuminate a pivotal causal axis uniting lipid metabolism, immune functionality, and sepsis outcomes, offering a fresh molecular lens into sepsis pathobiology and pinpointing potential therapeutic avenues to reduce the onset and mortality linked to this condition.