Causal effects of circulating lipids and lipid-lowering drugs on the risk of epilepsy: a two-sample Mendelian randomization study

Summary Background Previous studies have reported inconsistent results on the association between circulating lipids and lipid-lowering drugs with the risk of epilepsy. Aim To assess whether genetically predicted circulating lipids and lipid-lowering drugs are causally associated with the risk of epilepsy outcome. Methods We performed a two-sample Mendelian randomization (MR) analysis model to genetically predict the causal effects of circulating lipids (apolipoprotein A [APOA], apolipoprotein B [APOB], cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], lipoprotein A and triglycerides) and lipid-lowering drugs (HMG-CoA reductase [HMGCR] and proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors) on epilepsy. Nine MR analysis methods were conducted to analyze the final results. The inverse-variance weighted (IVW) method was used as the primary outcome. The other MR analysis methods (simple mode, weighted mode, simple median, weighted median, penalized weighted median, MR Egger and MR-Egger [bootstrap]) were conducted as the complement to IVW. In addition, the robustness of the MR analysis results was assessed by leave-one-out analysis. Results The IVW analysis method demonstrated that there is no causal association between circulating lipids (APOA: odds ratio [OR], 0.958, 95% confidence interval (CI), 0.728–1.261, P = 0.760; APOB: OR, 1.092; 95% CI, 0.979–1.219, P = 0.115; cholesterol: OR, 1.210; 95% CI, 0.981–1.494, P = 0.077; HDL-C: OR, 0.964; 95% CI, 0.767–1.212, P = 0.753; LDL-C: OR, 1.100; 95% CI, 0.970–1.248, P = 0.137; lipoprotein A: OR, 1.082; 95% CI, 0.849–1.379, P = 0.528; triglycerides: OR, 1.126; 95% CI, 0.932–1.360, P = 0.221) and lipid-lowering drugs (HMGCR inhibitors: OR, 0.221; 95% CI, 0.006–8.408, P = 0.878; PCSK9 inhibitors: OR, 1.112; 95% CI, 0.215–5.761, P = 0.902) with risk of epilepsy. The other MR analysis methods and further leave-one-out sensitivity analysis confirmed the robustness of final results. Conclusion This MR study demonstrated that there were no genetically predicted causal relationships between circulating lipids and lipid-lowering drugs with the risk of epilepsy.