Shen Yingjie, Wang Yaolou, Shen Yongze, Zhang Xi, Yu Zhao, Xu Hangjia, Lin Tie, Rong Yiwei, Guo Chunmei, Gao Aili, Liang Hongsheng
NHC Key Laboratory of Cell Transplantation, Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
School of Life Science, Northeast Agricultural University, Harbin, China.
J Neurochem. 2025 Jan;169(1):e16293. doi: 10.1111/jnc.16293.
Hemorrhagic stroke (HS) mainly includes intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), both of which seriously affect the patient's prognosis. Cerebrospinal fluid (CSF) metabolites and HS showed a link in observational studies. However, the causal association between them is not clear. We aimed to establish the optimal causality of CSF metabolites with HS. Mendelian randomization (MR) was employed to identify associations between CSF metabolites and different sources of HS. Univariable MR and false discovery rates (FDR) were used to identify initial causal associations. Linkage disequilibrium score regression determined genetic correlations. Multiple sensitive analyses ensured the reliability of the results. Multivariable MR and MR Bayesian Model Averaging were used to identify the optimal causal associations. The combined effects of metabolites and HS were assessed by meta-analyses. Pathway analyses were performed to identify potential pathways of action. Reverse MR was also conducted to identify reverse causal associations. Finally, Corresponding blood metabolites were used to explore the multiple roles of metabolites. We identified 20 CSF metabolites and six metabolic pathways associated with ICH; 15 CSF metabolites and three metabolic pathways associated with SAH. Nineteen and seven metabolites were causally associated with deep and lobar ICH, respectively. CSF levels of mannose (OR 0.63; 95% CI 0.45-0.88; P = 0.0059) and N-acetyltaurine (OR 0.68; 95% CI 0.47-0.98; P = 0.0395) may serve as the optimal exposures for ICH and SAH, respectively. Additionally, CSF ascorbic acid 3-sulfate levels significantly decrease the risk of deep ICH (OR 0.79; 95% CI 0.66-0.94; p = 0.0065; P = 0.091). Supplemental analysis of blood metabolites suggested multiple roles for CSF and blood N-formylanthranilic acid and hippurate. There are significant causal associations between CSF metabolites and HS, which provides a further rationale for the prevention and monitoring of ICH and SAH.
出血性卒中（HS）主要包括脑出血（ICH）和蛛网膜下腔出血（SAH），二者均严重影响患者预后。观察性研究表明脑脊液（CSF）代谢物与HS之间存在联系。然而，它们之间的因果关联尚不清楚。我们旨在确定CSF代谢物与HS之间的最佳因果关系。采用孟德尔随机化（MR）方法来识别CSF代谢物与不同类型HS之间的关联。单变量MR和错误发现率（FDR）用于识别初始因果关联。连锁不平衡评分回归确定遗传相关性。多次敏感性分析确保结果的可靠性。多变量MR和MR贝叶斯模型平均法用于识别最佳因果关联。通过荟萃分析评估代谢物与HS的联合效应。进行通路分析以识别潜在的作用途径。还进行了反向MR以识别反向因果关联。最后，使用相应的血液代谢物来探索代谢物的多种作用。我们识别出20种与ICH相关的CSF代谢物和6条代谢途径；15种与SAH相关的CSF代谢物和3条代谢途径。19种和7种代谢物分别与深部和叶性ICH存在因果关联。甘露糖的CSF水平（比值比[OR]0.63；95%置信区间[CI]0.45 - 0.88；P = 0.0059）和N - 乙酰牛磺酸的CSF水平（OR 0.68；95% CI 0.47 - 0.98；P = 0.0395）可能分别作为ICH和SAH的最佳暴露因素。此外，CSF中3 - 硫酸抗坏血酸水平显著降低深部ICH的风险（OR 0.79；95% CI 0.66 - 0.94；p = 0.0065；P = 0.091）。血液代谢物的补充分析表明CSF和血液中的N - 甲酰基邻氨基苯甲酸和马尿酸具有多种作用。CSF代谢物与HS之间存在显著的因果关联，这为ICH和SAH的预防和监测提供了进一步的理论依据。
