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=15

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=<sec id="sec1"><title>Background</title><p>Previous research has yielded conflicting results 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.</p></sec><sec id="sec2"><title>Methods</title><p>We used genetic instruments as proxies to the exposure of lipid-lowering drugs, employing variants within or near genes targeted by these drugs and associated with low-density lipoprotein cholesterol (LDL cholesterol) from a genome-wide association study. These variants served as controlling factors. Through drug target Mendelian randomization, we systematically assessed the impact of lipid-lowering medications, including HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and Niemann-Pick C1-like 1 (NPC1L1) inhibitors, on epilepsy.</p></sec><sec id="sec3"><title>Results</title><p>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, <italic>p</italic> = 0.01), focal epilepsy (OR = 1.24, 95% CI:1.08 to 1.43, <italic>p</italic> = 0.003), and focal epilepsy documented with lesions other than hippocampal sclerosis (OR = 1.05, 95% CI: 1.01 to 1.10, <italic>p</italic> = 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, <italic>p</italic> = 0.002). For other relationships, there was no reliable supporting data available.</p></sec><sec id="sec4"><title>Conclusion</title><p>The drug target MR investigation suggests a possible link between reduced epilepsy vulnerability and HMGCR and PCSK9 inhibition.</p></sec>