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

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  Figure 1.. The Directed Acyclic Graph (DAG) representing the Mendelian Randomisation (MR) framework employed to investigate the causal relationship between the circulating levels of systemic inflammatory regulators and sepsis. The MR analysis is guided by 3 crucial instrumental variable assumptions: (1) The instrumental variables must exhibit an association with the circulating levels of systemic inflammatory regulators (P < 5 × 10−8). (2) The instrumental variables must not be associated with any potential confounders that could influence the relationship between the circulating levels of systemic inflammatory regulators and sepsis. (3) The instrumental variables should solely impact the risk of sepsis through their influence on the the circulating levels of systemic inflammatory regulators. The instrumental variables are represented by SNPs, and the MR analysis employs the IVW method, Wald ratio, MR-Egger, Weighted-Median, Simple Mode, Weighted Mode and MR-PRESSO methods to estimate causal relationships. IVW = inverse variance weighted, SNPs = single nucleotide polymorphisms.

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  Figure 2.. Flow chart of this study.

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  Figure 3.. The causal association between between sepsis and circulating inflammatory factors when exposures were circulating inflammatory factors based on GWAS catalog. Inverse-variance weighting was regarded as the major method in this study. P value for heterogeneity based on Cochran’s Q statistic for IVW. CI = confidence internal, GWAS = gene-wide association study, IVW = inverse variance weighted, MR = mendelian randomization, nSNP = numbers of single nucleotide polymorphism, OR = odds ratio.

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  Figure 4.. The causal association between between sepsis and circulating inflammatory factors when exposures were circulating inflammatory factors based on IEU-open GWAS project. Inverse-variance weighting was regarded as the major method in this study. P value for heterogeneity based on Cochran’s Q statistic for IVW. CI = confidence internal, GWAS = gene-wide association study, IVW = inverse variance weighted, MR = mendelian randomization, nSNP = numbers of single nucleotide polymorphism, OR = odds ratio.

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  Figure 5.. The causal association of sepsis on circulating levels of systemic inflammatory regulators based on GWAS catalog. Inverse-variance weighting was regarded as the major method in this study. P value for heterogeneity based on Cochran’s Q statistic for IVW. CI = confidence internal, GWAS = gene-wide association study, IVW = inverse variance weighted, MR = mendelian randomization, nSNP = numbers of single nucleotide polymorphism, OR = odds ratio.

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  Figure 6.. The causal association of sepsis on circulating levels of systemic inflammatory regulators based on based on IEU-open GWAS project. Inverse-variance weighting was regarded as the major method in this study. P value for heterogeneity based on Cochran’s Q statistic for IVW. CI = confidence internal, GWAS = gene-wide association study, IVW = inverse variance weighted, MR = mendelian randomization, nSNP = numbers of single nucleotide polymorphism, OR = odds ratio.

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  Figure 7.. Scatter plots and Leave-one-out plots of circulating levels of systemic inflammatory regulators related SNPs with the risk of sepsis when outcome was spesis. Red lines in leave-one-out plots represent estimations from the IVW test. (A) and (B): Genetic association of TNF-related apoptosis-inducing ligand levels related SNPs and sepsis. (C) and (D): Genetic association of vascular endothelial growth factor A level related SNPs and sepsis. IVW = inverse variance weighted, SNPs = single nucleotide polymorphisms.

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  Figure 8.. Scatter plots and Leave-one-out plots of circulating levels of systemic inflammatory regulators related SNPs with the risk of sepsis when outcome were circulating levels of systemic inflammatory regulators. Red lines in leave-one-out plots represent estimations from the IVW test. (A) and (B): Genetic association of adenosine deaminase levels related SNPs and sepsis. (C) and (D): Genetic association of Interieukin-17A (IL-17A) level related SNPs and sepsis. (E) and (F): Genetic association of beta-nerve growth factor level related SNPs and sepsis. (G) and (H): Genetic association of DNER level related SNPs and sepsis. (I) and (J): Genetic association of Fibroblast growth factor 23 level related SNPs and sepsis. (K) and (L): Genetic association of Leukemia inhibitory factor level related SNPs and sepsis. (M) and (N): Genetic association of Monocyte chemoattractant protein-1 level related SNPs and sepsis. (O) and (P): Genetic association of Osteoprotegerin level related SNPs and sepsis. IVW = inverse variance weighted, SNPs = single nucleotide polymorphisms.