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<p>Intracranial aneurysms (IAs) represent the most prevalent form of cerebral vascular disease, characterized by their capacity to induce life-threatening subarachnoid hemorrhages (SAH). Prior investigations have highlighted notable changes in both pro-inflammatory and anti-inflammatory cytokine levels within the cerebrospinal fluid (CSF) of individuals harboring unruptured IAs. However, an insufficiency of research exists that specifically delves into the causal link between metabolites found in the cerebral spinal fluid and the presence of IAs.&#xa0;In the current study, Mendelian randomization (MR) analysis was employed as a methological approach to elucidate the causal connections between 338 CSF metabolites and IAs. The metabolic data were sourced from a comprehensive genome-wide association study (GWAS) summary dataset, which encompassed 291 participants. Concurrently, the GWAS datasets for IAs were procured from the work of Bakker et al., who compiled information on 7,495 aneurysm cases (including 5,425 ruptured and 2,070 unruptured) and a control group of 71,934 individuals. The estimation of causal effects was predominantly performed using the Inverse Variance Weighted (IVW) method.&#xa0;To achieve a broader perspective on the potential causal relationships between CSF metabolites and IAs, supplementary analyses were conducted utilizing MR-Egger regression, Weighted Median, Simple Mode, and Weighted Mode techniques. Additionally, to bolster the reliability of the findings, robustness checks for heterogeneity and pleiotropy were implemented. The MR analysis yielded a causal association between IAs and 12 recognized metabolites, along with three metabolites of unknown chemical nature. Elevated Sphingomyelin (d18:1/20:0, d16:1/22:0) concentrations, N-acetylglutamate levels, X-23,308, X-23,593, and X-24,452 were found to correlate with an augmented risk of IAs. Conversely, diminished risks of IAs were observed with lower 2-Hydroxyadipate, Citramalate, Glutamine, Glycine, Hippurate, Isocitrate, Isovalerate (i5:0), Octanoylcarnitine (c8), Ornithine, and Stachydrine levels. Reverse MR analysis indicates that there is a bidirectional causal relationship between IAs and 2-Hydroxyadipate. By clarifying the potential influence of CSF metabolites in the pathogenesis of IAs, this study provides new insights for the exploration of biomarkers for IAs, and offers ideas for more effective and targeted intervention in the treatment and prevention of this complex disease. Further exploration of these findings has the potential to yield enhanced management strategies and improved clinical outcomes for patients with IAs.</p>

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Mendelian randomization suggests a causal relationship between cerebrospinal fluid metabolites and intracranial aneurysms

  • 期刊论文

  • 发表日期：

    2025年10月16日

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  • Hao Yuan,
  • Xin Feng,
  • Zhuohua Wen,
  • Chi Huang,
  • Mengshi Huang,
  • Chuanzhi Duan

摘要

Intracranial aneurysms (IAs) represent the most prevalent form of cerebral vascular disease, characterized by their capacity to induce life-threatening subarachnoid hemorrhages (SAH). Prior investigations have highlighted notable changes in both pro-inflammatory and anti-inflammatory cytokine levels within the cerebrospinal fluid (CSF) of individuals harboring unruptured IAs. However, an insufficiency of research exists that specifically delves into the causal link between metabolites found in the cerebral spinal fluid and the presence of IAs. In the current study, Mendelian randomization (MR) analysis was employed as a methological approach to elucidate the causal connections between 338 CSF metabolites and IAs. The metabolic data were sourced from a comprehensive genome-wide association study (GWAS) summary dataset, which encompassed 291 participants. Concurrently, the GWAS datasets for IAs were procured from the work of Bakker et al., who compiled information on 7,495 aneurysm cases (including 5,425 ruptured and 2,070 unruptured) and a control group of 71,934 individuals. The estimation of causal effects was predominantly performed using the Inverse Variance Weighted (IVW) method. To achieve a broader perspective on the potential causal relationships between CSF metabolites and IAs, supplementary analyses were conducted utilizing MR-Egger regression, Weighted Median, Simple Mode, and Weighted Mode techniques. Additionally, to bolster the reliability of the findings, robustness checks for heterogeneity and pleiotropy were implemented. The MR analysis yielded a causal association between IAs and 12 recognized metabolites, along with three metabolites of unknown chemical nature. Elevated Sphingomyelin (d18:1/20:0, d16:1/22:0) concentrations, N-acetylglutamate levels, X-23,308, X-23,593, and X-24,452 were found to correlate with an augmented risk of IAs. Conversely, diminished risks of IAs were observed with lower 2-Hydroxyadipate, Citramalate, Glutamine, Glycine, Hippurate, Isocitrate, Isovalerate (i5:0), Octanoylcarnitine (c8), Ornithine, and Stachydrine levels. Reverse MR analysis indicates that there is a bidirectional causal relationship between IAs and 2-Hydroxyadipate. By clarifying the potential influence of CSF metabolites in the pathogenesis of IAs, this study provides new insights for the exploration of biomarkers for IAs, and offers ideas for more effective and targeted intervention in the treatment and prevention of this complex disease. Further exploration of these findings has the potential to yield enhanced management strategies and improved clinical outcomes for patients with IAs.