Objective To investigate the causal relationship between plasma tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) level and 28-day death from sepsis by two-sample Mendelian randomization. Methods Published genome-wide association studies were the data sources, from which single nucleotide polymorphisms significantly associated with 28-day death from sepsis were screened out to serve as instrumental variables. In order to evaluate the causal relationship between plasma TRAIL level and 28-day death from sepsis, 4 methods, including inverse variance weighted (IVW) method, MR-Egger analysis method, weighted median estimator method, and weighted mode method, were used to perform the two-sample MR analysis. Sensitivity analysis was performed using the leave-one-out method, heterogeneity test using the Cochran′s Q test, and the horizontal pleiotropy of the results using the MR-Egger intercepe test. Results A total of 10 strong instrumental variables were selected for the two-sample MR analysis. The results of IVW analysis showed that there was a causal relationship between plasma TRAIL level and 28-day death from sepsis [OR=1.186, 95% CI (1.004~1.339), P=0.044], which was supported by the other three analyses. Sensitivity analysis results showed that the MR analysis results were steady, heterogeneity test results showed that there was no heterogeneity among SNPs, and the pleiotropy analysis results showed that there was no horizontal pleiotropy in the instrumental variables (all P>0.05). The funnel plot showed that the results were unbiased. Conclusion There is a causal relationship between TRAIL and 28-day mortality from sepsis, and an elevated plasma TRAIL level increases the risk of 28-day death from sepsis.

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