Genetic determinants of circulating metabolites and the risk of stroke and its subtypes.

Background and purpose: 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. Methods: 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. Results: 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 × 10−7), especially for large‐artery atherosclerotic stroke (OR 1.34, 95% CI 1.19–1.52, p = 1.90 × 10−6). 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 × 10−3). 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. Conclusions: 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. [ABSTRACT FROM AUTHOR]