Systemic inflammatory regulators and risk of acute-on-chronic liver failure: A bidirectional mendelian-randomization study

Wang, Shengnan; Zhu, Hai‐Liang; Lin, Pei; Zhang, Mengyuan; Wan, Xiaoqiang; Xu, Hao; Hua, Ruimao; Zhu, Mingqin; Gao, Pujun

doi:10.3389/fcell.2023.1125233

Cited by 41 publications

(21 citation statements)

References 58 publications

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“…Therefore, our results support previous research linking IL-13 levels to CHB risk [34]. Low IL-13 levels are considered a marker of increased mortality in alcoholic hepatitis, whereas chronically elevated IL-13 levels are associated with a higher risk of worsening liver function [35]. Moreover, the impact of IL-13 on hepatic brosis and the compensatory proliferation of hepatocytes and biliary cells was independently and concurrently regulated in a model of liver disease progression induced by either IL-13 overexpression or infection [36].…”

Section: Discussionsupporting

confidence: 91%

Role of Circulating Inflammatory Proteins in Chronic Hepatitis B: A Two-Sample Mendelian Randomization Study.

Lin,

Chen

2024

Preprint

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Background: Alterations in circulating inflammatory proteins are strongly associated with the progression of chronic hepatitis B (Chon B); however, the nature of this causal relationship remains unclear. Therefore, we conducted two-sample Mendelian randomization (MR) to explore the association between circulating inflammatory proteins and CHB. Methods: Data for 91 circulating inflammatory proteins, including interleukin (IL)-10, tumor necrosis factor-alpha, and two CHB databases were sourced from the genome-wide association studies (GWAS) catalog and International Epidemiology Unit (IEU) Open GWAS project, respectively. MR analysis was performed using inverse variance weighting and several robustness, heterogeneity, and directionality checks, including MR-Egger, Cochran’s Q, MR-PRESSO, leave-one-out, and Steiger analyses. The variability of MR estimates for overlapping circulating inflammatory proteins across CHB datasets were evaluated using single nucleotide polymorphism (SNP) annotations of genes potentially linked to CHB infection. Results: We identified 4,044 SNPs associated with CHB and circulating inflammatory proteins; nine proteins correlated with CHB in the ebi-a-GCST90018804 dataset, whereas seven associated with CHB in the bbj-a-99 dataset. Heterogeneity assessment in both datasets excluded proteins with significant heterogeneity and confirmed the hypothesized direction of causality using Steiger’s test. Meta-analysis revealed that IL-13 was associated with an increased CHB risk, whereas monocyte chemoattractant protein-3 (MCP-3) was associated with a decreased risk; these effects were consistent across the two datasets. An additional 32 genes associated with CHB infection were identified. Conclusion: IL-13 and MCP-3 demonstrate a causal relationship with CHB; they hold promise as inflammatory markers of CHB risk and potential targets for future therapeutic strategies against this disease.

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Section: Discussionsupporting

confidence: 91%

Role of Circulating Inflammatory Proteins in Chronic Hepatitis B: A Two-Sample Mendelian Randomization Study.

Lin,

Chen

2024

Preprint

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“…For the MR data analysis, we utilized the “TwoSampleMR” package in the R. The inverse-weighted variance analysis was used to determine the causal relationship between the exposure factors and the outcome ( Chen et al, 2020 ; Zagkos et al, 2022 ; Wang et al, 2023 ). To assess heterogeneity among the study samples, MR-Egger and inverse variance-weighted functions in Cochran’s Q test were utilized, with a significance level of p >0.05 indicating non-heterogeneity.…”

Section: Methodsmentioning

confidence: 99%

Association between atorvastatin and erectile dysfunction: a comprehensive analysis incorporating real-world pharmacovigilance and Mendelian randomization

Chen,

Huang,

Chen

et al. 2024

Front. Pharmacol.

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Background:Atorvastatin is a commonly prescribed medication for the prevention of cardiovascular diseases. Recent observational studies have suggested a potential association between atorvastatin use and the occurrence of Erectile Dysfunction (ED). In this study, we aimed to explore the relationship between atorvastatin and ED using real-world data from the FAERS database and employed Mendelian randomization to assess causality.Methods:To evaluate the disproportionality of atorvastatin in relation to ED, we conducted several pharmacovigilance analyses, including odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence propagation neural network (BCPNN), and gamma-Poisson contractile apparatus (GPS). Additionally, we employed Mendelian randomization to investigate the causal relationship between atorvastatin and ED.Results:Pharmacovigilance disproportionality analysis revealed a significant association between atorvastatin and ED, as indicated by the following results: ROR [3.707078559, 95% CI (3.33250349, 4.123756054)], PRR [3.702969038, χ2 (669.2853829)], IC [1.870490139, IC025 (1.702813857)], and EBGM [3.656567867, EBGM05 (3.28709656)]. Furthermore, the two-sample Mendelian randomization analysis provided evidence supporting a causal relationship between atorvastatin use and ED, with an inverse variance weighted estimate of β = 3.17 (OR = 23.91, p = 0.02 < 0.05).Conclusion:Based on comprehensive analyses incorporating pharmacovigilance and Mendelian randomization, our findings suggest that atorvastatin use is associated with an increased risk of ED and indicate a causal relationship. These results emphasize the importance of considering potential adverse effects, such as ED, when prescribing atorvastatin for cardiovascular disease prevention. Further research and clinical monitoring are warranted to better understand the underlying mechanisms and develop appropriate strategies to mitigate this side effect.

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“…Additionally, supplementary sensitivity analyses were conducted using weighted mode and simple mode analyses. In cases where the IVW analysis yielded significant results ( p < 0.05) and no evidence of horizontal pleiotropy or heterogeneity was observed, the findings could be considered positive, even if the other methods did not yield significant results, as long as the direction of the β ‐values remained consistent [26]. In situations where horizontal pleiotropy was present but no heterogeneity was detected, the MR‐Egger method was employed.…”

Section: Methodsmentioning

confidence: 99%

Exploring causal association between circulating inflammatory cytokines and functional outcomes following ischemic stroke: A bidirectional Mendelian randomization study

Liu,

Huang

et al. 2023

Euro J of Neurology

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ObjectivesPrevious observational studies have indicated correlations between various inflammatory cytokines and functional outcomes following ischemic stroke (IS); however, the causality remains unclear. We aimed to further evaluate the causal association between 41 circulating inflammatory cytokines and functional outcomes following IS.MethodsTwo‐sample bidirectional Mendelian randomization (MR) analysis was used in this study. The genetic variation of 41 circulating inflammatory cytokines were derived from genome‐wide association study (GWAS) data of European ancestry (n = 8293). The corresponding genetic association of functional outcomes following IS were derived from European ancestry GWAS data (n = 6021).ResultsInverse variance weighted (IVW) analysis showed that genetically predicted increased levels of regulation and activation in normal T‐cell expression and secretion factor (RANTES/CCL5) and eosinophilic chemotactic factor (EOTAXIN/CCL11) were positively correlated with the increased adverse functional outcomes (modified Rankin Scale [mRS≥3] following IS (OR: 1.40, 95% CI: 1.002–1.96, p = 0.049; OR: 1.33, 95% CI: 1.15–1.54, p = 0.0001). Interleukin 18 (IL‐18) level might be the downstream consequence of adverse functional outcomes following IS (β: −0.09, p = 0.039). Other inflammatory cytokines and functional outcomes following IS did not appear to be causally related.ConclusionsThis study suggests a causality between inflammation and adverse functional outcomes following IS. RANTES (CCL5) and EOTAXIN (CCL11) may be the upstream factors of adverse functional outcomes following IS, while IL‐18 may be the downstream effect of adverse functional outcomes following IS. Whether these cytokines can be used to predict or improve adverse functional outcomes after IS requires further researches.

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Systemic inflammatory regulators and risk of acute-on-chronic liver failure: A bidirectional mendelian-randomization study

Cited by 41 publications

References 58 publications

Role of Circulating Inflammatory Proteins in Chronic Hepatitis B: A Two-Sample Mendelian Randomization Study.

Role of Circulating Inflammatory Proteins in Chronic Hepatitis B: A Two-Sample Mendelian Randomization Study.

Association between atorvastatin and erectile dysfunction: a comprehensive analysis incorporating real-world pharmacovigilance and Mendelian randomization

Exploring causal association between circulating inflammatory cytokines and functional outcomes following ischemic stroke: A bidirectional Mendelian randomization study

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