Causal Effects of Circulating Lipids and Lipid-lowering Drugs on The Risk of Epilepsy: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Previous studies have reported inconsistent results on the association between circulating lipids and lipid-lowering drugs with the risk of epilepsy.

OBJECTIVE: 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, 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 was no genetically predicted causal relationships between circulating lipids and lipid-lowering drugs with the risk of epilepsy.