Eur J Neurol. 2022 Sep 10. doi: 10.1111/ene.15549. Online ahead of print.
ABSTRACT
BACKGROUND: Circulating metabolites have been implicated in stroke pathogenesis, but their genetic determinants is understudied. Using Mendelian randomization approach, we aim to provide evidence for the relationship of circulating metabolites on risk of stroke and its subtypes.
METHODS: Genetic instruments of 102 circulating metabolites were obtained from a genome-wide association study (GWAS), including 24,925 European individuals. Stroke were extracted from MEGASTROKE dataset (67,162 cases; 454,450 controls) and lacunar stroke dataset (7338 cases; 254,798 controls). The magnetic resonance imaging (MRI) markers of cerebral small vessel diseases (CSVD) and microstructural injury were evaluated by GWAS 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 primary analytical method, and directional pleiotropy and heterogeneity were examined in sensitivity analyses.
RESULTS: Genetic predisposition to higher level of cholesterol in small and low-density lipoprotein (LDL) were associated with risk of stroke (OR[95%CI]=1.14[1.08-1.21], p=5.98*10-7 ), especially for large-artery atherosclerotic stroke (OR[95%CI]=1.34[1.19-1.52], p=1.90*10-6 ). Total lipids in LDL particles were also associated with risk of stroke. Genetically determined higher cholesterol level in high-density lipoprotein (HDL-C) was associated with risk of intracerebral hemorrhage (OR[95%CI]=1.74[1.23-2.45], p=1.66*10-3 ). No statistically significant association was found between genetic predisposition to circulating metabolites and MRI markers of CSVD and microstructural injury.
CONCLUSIONS: Genetically determined levels of lipids in small LDL were associated with the risk of stroke, suggesting a therapeutic strategy targeting small LDL levels may be crucial for stroke prevention. HDL-C was positively associated with the risk of intracerebral hemorrhage.
PMID:36086915 | DOI:10.1111/ene.15549
