A bidirectional mendelian-randomization analyses of genetically predicted circulating levels of systemic inflammatory regulators with risk of sepsis

Whether there is a causal relationship between circulating levels of systemic inflammatory regulators and sepsis remains unclear. To determine whether genetically predicted circulating levels of cytokines are associated with risk of sepsis, a bidirectional two-sample Mendelian randomization (MR) analysis based on the a STROBE-compliant cross-sectional observational study was conducted utilizing gene-wide association study (GWAS) data. Selected with rigor, single-nucleotide polymorphisms served as instrumental variables for subsequent MR analysis. The preferred method for the MR analysis was the inverse-variance weighted approach. However, for comprehensive sensitivity analyses, 6 additional MR methods were employed. Cochrane's Q test was performed to examine heterogeneity. A leave-one-out method ensured the stability of MR results. Our findings suggest an inverse association between the levels of beta-nerve growth factor (BNGF) and the risk of sepsis development (OR = 0.769, 95% CI = 0.599-0.987, P = .039). In contrast, higher levels of TNF-related apoptosis-inducing ligand and vascular endothelial growth factor A (VEGF-A) are positively correlated with sepsis risk (OR = 1.094, 95% CI = 1.012-1.183, P = .025; OR = 1.182, 95% CI = 1.016-1.375, P = .031, respectively). Reverse MR Analysis indicated that sepsis risk is linked with lower circulating levels of adenosine deaminase and Interleukin-17A (β = -0.043, 95% CI = -0.085 to -0.002, P = .042; β = -0.061, 95% CI = -0.108 to -0.013, P = .012, respectively), and also with higher circulating levels of BNGF, delta/notchlike epidermal growth factor-related receptor, fibroblast growth factor 23, leukemia inhibitory factor, monocyte chemoattractant protein-1, and osteoprotegerin (β = 0.056, 95% CI = 0.015-0.096, P = .007; β = 0.137, 95% CI = 0.035-0.240, P = .009; β = 0.118, 95% CI = 0.020-0.216, P = .018; β = 0.136, 95% CI = 0.020-0.252, P = .022; β = 0.143, 95% CI = 0.043-0.242, P = .005; β = 0.116, 95% CI = 0.010-0.222, P = .031, respectively). Sum up, our study provides evidence supporting a bidirectional causal relationship between sepsis and genetically predicted circulating levels of systemic inflammatory regulators.