Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Eur J Neurol. 2022 Dec;29(12):3711-3719. doi: 10.1111/ene.15549. Epub 2022 Sep 23.
Circulating metabolites have been implicated in stroke pathogenesis, but their genetic determinants are understudied. Using a Mendelian randomization approach, our aim was to provide evidence for the relationship of circulating metabolites and the risk of stroke and its subtypes.
Genetic instruments of 102 circulating metabolites were obtained from a genome-wide association study, including 24,925 European individuals. Stroke was extracted from the MEGASTROKE dataset (67,162 cases; 454,450 controls) and a lacunar stroke dataset (7338 cases; 254,798 controls). The magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury were evaluated by a genome-wide association study of white matter hyperintensities (N = 18,381), fractional anisotropy (N = 17,663), mean diffusivity (N = 17,467) and brain microbleeds (N = 25,862). The inverse-variance weighted method Mendelian randomization was used as the primary analytical method, and directional pleiotropy and heterogeneity were examined in sensitivity analyses.
A genetic predisposition to a higher level of cholesterol in small and low-density lipoprotein (LDL) was associated with risk of stroke (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.08-1.21, p = 5.98 × 10 ), especially for large-artery atherosclerotic stroke (OR 1.34, 95% CI 1.19-1.52, p = 1.90 × 10 ). Total lipids in LDL particles were also associated with risk of stroke. A genetically determined higher cholesterol level in high-density lipoprotein (HDL-C) was associated with risk of intracerebral haemorrhage (OR 1.74, 95% CI 1.23-2.45, p = 1.66 × 10 ). No statistically significant association was found between genetic predisposition to circulating metabolites and magnetic resonance imaging markers of cerebral small vessel disease and microstructural injury.
Genetically determined levels of lipids in small LDL were associated with the risk of stroke, suggesting that a therapeutic strategy targeting small LDL levels may be crucial for stroke prevention. HDL-C was positively associated with the risk of intracerebral haemorrhage.
循环代谢物与中风发病机制有关，但对其遗传决定因素的研究较少。本研究采用孟德尔随机化方法，旨在为循环代谢物与中风及其亚型风险之间的关系提供证据。
从全基因组关联研究中获得了 102 种循环代谢物的遗传工具，包括 24925 名欧洲个体。从 MEGASTROKE 数据集（67162 例病例；454450 例对照）和腔隙性卒中数据集（7338 例病例；254798 例对照）中提取中风数据。通过脑白质高信号的全基因组关联研究（N=18381）、各向异性分数（N=17663）、平均扩散系数（N=17467）和脑微出血（N=25862）来评估脑小血管病和微观结构损伤的磁共振成像标志物。采用逆方差加权孟德尔随机化作为主要分析方法，并在敏感性分析中检查了定向异质性和异质性。
小而低密度脂蛋白（LDL）中胆固醇水平升高的遗传倾向与中风风险相关（比值比[OR]1.14，95%置信区间[CI]1.08-1.21，p=5.98×10-8），尤其是大动脉粥样硬化性中风（OR 1.34，95%CI 1.19-1.52，p=1.90×10-8）。LDL 颗粒中的总脂质也与中风风险相关。高密度脂蛋白（HDL-C）中胆固醇水平升高的遗传倾向与脑出血风险相关（OR 1.74，95%CI 1.23-2.45，p=1.66×10-8）。未发现循环代谢物的遗传倾向与脑小血管病和微观结构损伤的磁共振成像标志物之间存在统计学显著关联。
小 LDL 中脂质的遗传水平与中风风险相关，表明针对小 LDL 水平的治疗策略可能对预防中风至关重要。HDL-C 与脑出血风险呈正相关。
