AUTHOR=Huang Shicun , Liu Yuan , Zhang Yi , Wang Yiqing , Gao Ya , Li Runnan , Yu Lidong , Hu Xiaowei , Fang Qi 

TITLE=Analyzing the causal relationship between lipid-lowering drug target genes and epilepsy: a Mendelian randomization study

JOURNAL=Frontiers in Neurology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1331537

DOI=10.3389/fneur.2024.1331537

ISSN=1664-2295

ABSTRACT=Background: Previous research has yielded conflicting findings on the link between epilepsy risk and lipid-lowering medications. The aim of this study is to determine whether the risk of epilepsy outcomes is causally related to lipid-lowering medications predicted by genetics.We used genetic instruments to proxy the exposure of lipid-lowering drugs, employing variants within or near genes targeted by these drugs and associated with low-density lipoprotein (LDL cholesterol) from a genome-wide association study.These variants served as controlling factors. Through drug-target Mendelian 2 / 15 randomization, we systematically assessed the impact of lipid-lowering medications, including HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors, on epilepsy.The analysis demonstrated that a higher expression of HMGCR was associated with an elevated risk of various types of epilepsy, including all types [OR= 1.17, 95% CI:1.03 to 1.32, P = 0.01], focal epilepsy [OR=1.24, 95% CI:1.08 to 1.43, P = 0.003],and focal epilepsy with lesions other than hippocampal sclerosis [OR=1.05, 95% CI:1.01 to 1.10, P = 0.02]. The risk of juvenile absence epilepsy (JAE) was also associated with higher expression of PCSK9 [OR=1.06, 95% CI: 1.02 to 1.09, P = 0.002]. For other relationships, there was no reliable supporting data available.The drug-target MR investigation suggests a possible link between reduced epilepsy vulnerability and HMGCR and PCSK9 inhibition.