Non‐alcoholic fatty liver disease and stroke: A Mendelian randomization study

Abstract Background The association between non‐alcoholic fatty liver disease (NAFLD) and the risk of stroke is heterogeneous. Therefore, we aimed to examine any potential causal relationship between these two traits through Mendelian randomization. Methods The genetic instruments associated with NAFLD were selected from a large genome‐wide association study in individuals of European ancestry (1483 cases and 17,781 controls, replicated in 559 cases and 945 controls). The genetic associations for stroke (40,585 cases and 406,111 controls) and ischemic stroke (34,217 cases and 406,111 controls) were selected from the MEGASTROKE consortium of European ancestry participants. The causal effects on ischemic stroke subtypes, including large artery atherosclerosis (LAA) (4373 cases and 146,392 controls), small vessel occlusion (SVO) (5386 cases and 192,662 controls), and cardioembolic stroke (7193 cases and 204,570 controls), were also analyzed. The inverse variant weighted method was performed to obtain the casual estimates. Heterogeneity and pleiotropy of individual single nucleotide polymorphisms were also tested for the robustness of the results. Results NAFLD was not associated with stroke (odds ratio [OR] 1.015; 95% confidence interval [CI] 0.996–1.034; p = 0.121) and ischemic stroke (OR 1.017; 95% CI 0.997–1.037; p = 0.092). Regarding ischemic stroke subtypes, there were positive causal inferences on LAA (OR 1.065; 95% CI 1.004–1.129; p = 0.037) and SVO (OR 1.058; 95% CI 1.003–1.116; p = 0.037), while it was not significant for cardioembolic stroke (OR 1.026; 95% CI 0.983–1.071; p = 0.243). Conclusion This study suggests that the potential causal effect of NAFLD on ischemic stroke may be confined to the LAA and SVO subtypes.