Association of Interleukin-6 Signaling and C-Reactive Protein With Intracranial Aneurysm: A Mendelian Randomization and Genetic Correlation Study

Niu, Peng-Peng; Wang, Xue; Xu, Yuming

doi:10.3389/fgene.2021.679363

Cited by 9 publications

(5 citation statements)

References 46 publications

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“…Result of the present study was consistent with previous research which observed significantly higher cerebrospinal fluid level of GRO-alpha in uIA patients [ 50 ]. Our result was supported by a previous MR study which showed sIL6R and CRP levels were not associated with IA [ 8 ]. Our finding was partially contradictory to a meta-analysis, which found no evidence of IL-1α, IL-1β, IL-6, and IL-12β against IA, but identified significant association of TNF-α polymorphism with IA [ 51 ].…”

Section: Discussionsupporting

confidence: 90%

“…Recent studies have utilized MR to explore the casual relationship between IA and various risk factors, with only one study examining potential inflammatory mechanism. With a hypothesis-driven design, previous MR study have revealed sIL6R and C-reactive protein (CRP) levels were not associated with IA risk [ 8 ]. Given these uncertainties, we designed this MR study to further assesses whether causality exists between inflammatory biomarkers and IA.…”

Section: Introductionmentioning

confidence: 99%

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Circulating inflammatory biomarkers and risk of intracranial aneurysm: a Mendelian randomization study

Fang,

Cao,

2024

Eur J Med Res

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Background Intracranial aneurysm (IA) accounts for a substantial source of non-traumatic subarachnoid hemorrhage, with inflammation postulated as a potential factor in its pathogenesis. The present study aims at evaluating the association between circulating inflammatory cytokines and risk of IA under a bidirectional two-sample Mendelian randomization (MR) design. Methods For primary analysis, summary statistics of inflammatory regulators was obtained from a genome-wide association study (GWAS) comprising 8293 Finnish participants. Summary data of IA were extracted from a GWAS which comprised 7495 cases and 71,934 controls in European descent. For targeted analysis, summary statistics were extracted from two proteomic studies, which recruit 3301 and 5368 European participants, respectively. Summary data of IA were acquired from FinnGen study with 5342 cases and 342,673 controls. We employed inverse variance weighted (IVW) method as main approach, with sensitivity analyses using weighted median, MR-Egger, and MR-PRESSO methods. Reverse MR analyses were conducted to minimize bias from reverse causality. Results No causation of cytokines with IA subtypes was identified in both primary and targeted analysis after Bonferroni correction. In primary analysis, vascular endothelial growth factor (VEGF) and fibroblast growth factor basic (bFGF) levels were suggestively associated with aneurysmal subarachnoid hemorrhage (aSAH) [VEGF → aSAH: OR = 1.15, 95%CI 1.04–1.26, P = 0.005; bFGF → aSAH: OR = 0.62, 95% CI 0.42–0.92, P = 0.02]. Statistical significance failed to replicate in targeted analysis. Instead, suggestive protective effects for aSAH were identified in FGF-9 (FGF-9 → aSAH: OR = 0.74, 95% CI 0.62–0.89, P = 0.001) and FGF-16 (FGF-16 → aSAH: OR = 0.84, 95% CI 0.72–0.97, P = 0.017). Furthermore, reverse analyses identified suggestive effect of unruptured IA on RANTES, MIF, GRO-alpha, FGF-16, and FGF-19. Result remained robust after applying sensitivity tests. Conclusions No causality of inflammatory biomarkers on the risk of IA subtypes was identified. Future large-scale studies are in need to evaluate the temporal dynamics of cytokines in conjunction with IA.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Circulating inflammatory biomarkers and risk of intracranial aneurysm: a Mendelian randomization study

Fang,

Cao,

2024

Eur J Med Res

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“…Additionally, we preliminarily assessed the genetic overlap between EoE and IBD (data from the ieu-a-31 GWAS dataset) via the linkage disequilibrium score regression ( 38 ), and the result showed no evidence of a genetic correlation between the two diseases (genetic correlation = −0.325, p = 0.393). Generally, a consistency between results of linkage disequilibrium score regression and MR could make the MR estimates more convincing ( 39 ). Therefore, results generated by this study should still be interpreted with caution.…”

Section: Discussionmentioning

confidence: 99%

Causal relationship between eosinophilic esophagitis and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study

Ji,

Zhi

2024

Front. Immunol.

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BackgroundEosinophilic esophagitis (EoE) and inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), are immune-mediated gastrointestinal diseases with overlapped pathogenesis and are sometimes concurrently diagnosed, but their causal relationship remains unclear. We investigated the causal relationship between EoE and IBD and its subtypes via a two-sample bidirectional Mendelian randomization (MR) approach.MethodsMR analyses were performed using summary data of a genome-wide association study (GWAS) on individuals of European ancestry. Independent single-nucleotide polymorphisms correlated with EoE (from a GWAS meta-analysis containing 1,930 cases and 13,634 controls) and IBD (from FinnGen GWASs containing 9,083 IBD, 2,033 CD, and 5,931 UC cases, and GWASs of IBD genetic consortium containing 12,882 IBD, 6,968 UC, and 5,956 CD cases) were selected as instruments. We applied the inverse variance weighted (IVW) method as the primary analysis followed by several sensitivity analyses. For the forward MR study, estimates from IVW methods were subsequently meta-analyzed using a random-effect model.ResultsOur results suggested a causal effect of EoE on IBD [pooled odds ratio (OR), 1.07; 95% confidence interval (CI), 1.02–1.13] and EoE on UC (pooled OR, 1.09, 95% CI, 1.04–1.14). No causal link between EoE and CD was observed (pooled OR, 1.05; 95% CI, 0.96–1.16). The reverse MR analyses revealed no causal effect of IBD (and its subtypes) on EoE. Sensitivity analyses confirmed the robustness of primary results.ConclusionsOur findings provided evidence of a suggestive causal effect of EoE on IBD (specifically on UC) in the European population. Increased awareness of concurrent or subsequent IBD in patients with EoE is called for. Still, the present evidence is not adequate enough and ought to be validated by further investigations.

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“…There are few studies demonstrating such associations. A study examining soluble IL-6 receptor and CRP levels to intracranial aneurysm risk showed no association despite other studies showing high CRP levels related to fusiform intracranial aneurysm presence and IL-6 polymorphisms related to intracranial aneurysm presence [16][17][18]. Additional cytokines have been examined in healthy patients with intracranial aneurysms, noting elevated levels of IL-1B, TNF-alpha, and MCP-1 in those with aneurysms [19].…”

Section: Discussionmentioning

confidence: 99%

Uncontrolled HIV and inflammation is associated with intracranial saccular aneurysm presence

Dugue¹,

Schnall²,

Liu³

et al. 2022

Aids

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Objective:To study biomarkers of inflammation in cerebrovascular disease, exploring modifiable and non-modifiable biochemical and clinical risk factors associated with the presence of intracranial saccular aneurysms (ISAs) in an HIV-positive cohort.Design:A cross-sectional community-based study was used to study blood biomarkers of inflammation as predictors of cerebrovascular disease, specifically the presence of ISAs in persons with HIV. Potential biochemical and clinical predictors of ISA presence were identified.Methods:Time of flight magnetic resonance angiography and magnetic resonance imaging data identified the presence of ISAs in an HIV-positive cohort. Quantitative assays for neuroinflammatory biomarkers were performed on plasma blood samples. Lasso regression models were used to identify neuroinflammatory biomarkers and clinical risk factors associated with ISAs.Results:Eight of 72 participants had radiographically identified ISAs. ISAs were more common in non-Hispanic black participants (18.5% vs. 0% presence in nonblack patients). Participants with well controlled HIV (defined as CD4+ count >200 cells/ml and undetectable viral load at time of magnetic resonance imaging) had lower odds of ISAs (odds ratio: 0.19, 95% confidence interval 0.05–0.79) independent of age, sex, ethnicity and vascular risk factors. Macrophage inflammatory protein-1 p, an HIV- suppressive factor detected in participant blood samples, was inversely associated with aneurysm presence.Conclusion:Well controlled HIV is associated with fewer ISAs. The identification of non-modifiable and modifiable risk factors contributing to ISA formation may provide valuable insight to impact clinical practice and inform the pathophysiology underlying ISA formation.

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Association of Interleukin-6 Signaling and C-Reactive Protein With Intracranial Aneurysm: A Mendelian Randomization and Genetic Correlation Study

Cited by 9 publications

References 46 publications

Circulating inflammatory biomarkers and risk of intracranial aneurysm: a Mendelian randomization study

Circulating inflammatory biomarkers and risk of intracranial aneurysm: a Mendelian randomization study

Causal relationship between eosinophilic esophagitis and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study

Uncontrolled HIV and inflammation is associated with intracranial saccular aneurysm presence

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