Abstract
OBJECTIVE: This study evaluates the potential protective effects of statins against epilepsy, focusing on their differential impacts on focal and generalized epilepsy. It investigates the role of statins through the HMGCR gene and associated low-density lipoprotein (LDL) cholesterol levels. METHODS: A two-sample Mendelian randomization (MR) and summary-data-based MR (SMR) approach were employed using genetic instruments from genome-wide association studies (GWASs) and expression quantitative trait loci (eQTLs). Subgroup analyses examined focal and generalized epilepsy, with sensitivity tests, including MR-Egger regression and MR-PRESSO, to assess horizontal pleiotropy and robustness. RESULTS: SMR analysis found no significant association between HMGCR expression and epilepsy risk across subtypes (p > 0.05). However, inverse-variance-weighted MR (IVW-MR) showed that elevated LDL cholesterol mediated by HMGCR was linked to an increased risk of focal epilepsy (OR = 1.251, 95% CI = 1.135-1.378). No such association was observed for generalized epilepsy. Statins showed promise in reducing post-stroke epilepsy risk, likely through anti-inflammatory and neuroprotective effects. SIGNIFICANCE: The findings suggest that statins' protective effects may be subtype-specific, particularly in post-stroke focal epilepsy. Further research is needed to elucidate underlying mechanisms and optimize their therapeutic potential in epilepsy management. PLAIN LANGUAGE SUMMARY: Statins, drugs typically used to manage cholesterol, may also lower the risk of developing certain types of epilepsy, especially post-stroke focal epilepsy, by reducing inflammation and protecting brain cells. The research found no clear effect of statins on generalized epilepsy or epilepsy caused by other factors. These results could aid in creating better treatments for epilepsy in the future.