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BackgroundSepsis and its complications pose a major global health burden. Mendelian randomization (MR) provides a genetic approach to assess causality.MethodsWe conducted a two-sample Mendelian randomization (MR) study using data from large-scale genome-wide association studies (GWAS). This study aimed to assess the causal effects of six key biomarkers (D-dimer, Galectin-3, activated protein C, tumor necrosis factor receptor 2, interleukin-6 receptor subunit alpha, and thrombomodulin) on six sepsis-related complications, including acute respiratory distress syndrome (ARDS) and acute renal failure. The primary analysis utilized the inverse-variance weighted (IVW) method, with comprehensive sensitivity analyses to assess for heterogeneity and pleiotropy. A False Discovery Rate (FDR) was applied to correct for multiple testing.ResultsThe primary IVW analysis suggested several potential causal associations. Genetically predicted D-dimer was associated with a lower risk of ARDS (OR = 0.63, P = 0.025), IL-6Rα with a reduced risk of acute renal failure (OR = 0.85, P = 0.035), and Galectin-3 with a lower risk of streptococcal septicaemia (OR = 0.95, P = 0.039). Reverse MR analysis suggested that genetic liability to sepsis (critical care) was associated with lower D-dimer levels. However, after FDR correction, none of these associations remained statistically significant. Sensitivity analyses did not indicate the presence of significant horizontal pleiotropy.ConclusionThis study did not find robust genetic evidence to support a causal relationship between the six selected biomarkers and the risk of sepsis-related complications after correction for multiple testing. The suggestive associations observed prior to correction warrant further investigation.