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

Abstract

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.

Causality of genetically determined metabolites and metabolic pathways on asthenia: a two-sample Mendelian randomization study

“…Due to the random assignation of the genetic variants during gametogenesis and freedom from external instances, MR prioritizes immunizing the results from the interference of confounding factors and reverse causality. It has been widely used for assessing the disease risk with metabolites [13][14][15][16][17] . There is a lack of MR studies utilized to trace the causal association between metabolites and asthenia.…”

Assessing the causal effect of genetically predicted metabolites and metabolic pathways on stroke

“…Previous studies have utilized MR analysis to assess the stroke risk with metabolites [22][23][24]. Nevertheless, they have been limited in their comprehensiveness.…”