Abstract
BACKGROUND: In observational studies, sepsis and circulating levels of cytokines have been associated with unclear causality. This study used Mendelian randomization (MR) to identify the causal direction between circulating cytokines and sepsis in a two-sample study. METHODS: An MR analysis was performed to estimate the causal effect of 41 cytokines on sepsis risk. The inverse-variance weighted random-effects method, the weighted median-based method, and MR-Egger were used to analyze the data. Heterogeneity and pleiotropy were assessed using MR-Egger regression and Cochran's Q statistic. RESULTS: Genetically predicted beta-nerve growth factor (OR = 1.12, 95% CI [1.037-1.211], P = 0.004) increased the risk of sepsis, while RANTES (OR = 0.92, 95% CI [0.849-0.997], P = 0.041) and fibroblast growth factor (OR = 0.869, 95% CI [0.766-0.986], P = 0.029) reduced the risk of sepsis. These findings were robust in extensive sensitivity analyses. There was no clear association between the other cytokines and sepsis risk. CONCLUSION: The findings of this study demonstrate that beta-nerve growth factor, RANTES, and fibroblast growth factor contribute to sepsis risk. Investigations into potential mechanisms are warranted.