• Weifeng Shang, Hang Qian, Sheng Zhang, Mingyang Yuan, Xiaojun Pan, Sisi Huang, Jiao Liu, and Dechang Chen.
• Department of Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
• Eur. J. Clin. Invest. 2024 Apr 1; 54 (4): e14145e14145.

BackgroundEvidence supports the observational correlations between human blood metabolites and sepsis. However, whether these associations represent a causal relationship is unknown. In this study, we applied two-sample Mendelian randomization (MR) analyses to examine causality between genetically proxied 486 blood metabolites and sepsis risk.MethodsWe used summary data from genome-wide association studies (GWAS) on 486 metabolites involving 7824 individuals as exposure and a sepsis GWAS including 11,643 cases and 474,841 controls as the outcome. The inverse-variance weighted (IVW) was the primary method to estimate the causal relationship between exposure and outcome, with MR-Egger and weighted median serving as supplements. Sensitivity analyses were implemented with Cochrane's Q test, MR-Egger intercept, MR-PRESSO and leave-one-out analysis. In addition, we performed replication MR, meta-analysis, Steiger test, linkage disequilibrium score (LDSC) regression and multivariable MR (MVMR) to thoroughly verify the causation.ResultsWe identified that genetically determined high levels of 1-oleoylglycerophosphoethanolamine (odds ratio (OR) = .52, 95% confidence interval (CI): .31-.87, p = .0122), alpha-glutamyltyrosine (OR = .75, 95% CI: .60-.93, p = .0102), heptanoate (7:0) (OR = .51, 95% CI: .33-.81, p = .0041) and saccharin (OR = .84, 95% CI: .74-.94, p = .0036) were causally associated with a lower risk of sepsis. MVMR analysis demonstrated the independent causal effect of these metabolites on sepsis.ConclusionsThese findings indicated that four blood metabolites have a protective impact on sepsis, thus providing novel perspectives into the metabolite-mediated development mechanism of sepsis by combining genomics and metabolomics.© 2023 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.

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