The class
Drug-target Mendelian randomization finds genetically proxied CETP inhibition protects against subarachnoid hemorrhage with no safety signal (Eur Stroke J 2025)
Original title: Novel insights into causal effects of serum lipids, lipid metabolites, and lipid-modifying targets on the risk of intracerebral aneurysm
This study used Mendelian randomization to test causal relationships between serum lipids, 249 lipid metabolic traits, and 10 lipid-lowering drug targets and the risk of intracerebral aneurysm (IA), using instrumental variants from the largest available genome-wide association studies. After correcting for multiple comparisons, genetically proxied triglycerides (OR 1.25, p = 0.005) and HDL cholesterol (OR 0.93, p = 0.008) showed causal relationships with IA risk, and four lipid metabolic traits were causally linked to IA (p less than 0.0002). Drug-target Mendelian randomization confirmed that genetically proxied HMGCR, ANGPTL3, and CETP inhibition remained statistically significantly associated with reduced risk of subarachnoid hemorrhage after multiple-testing correction (p less than 0.005), and phenome-wide Mendelian randomization found no other diseases linked to these lipid-lowering targets, supporting a beneficial, safety-neutral causal effect of CETP inhibition on this outcome and opening a new potential treatment avenue for intracerebral aneurysm.
Original abstract
Introduction: Different serum lipid and lipid-lowering agents are reported to be related to the occurrence of intracerebral aneurysm (IA). However, the causal relationship between them requires further investigation.
Patients And Methods: Mendelian randomization (MR) analysis was performed on IA and its subtypes by using instrumental variants associated with six serum lipids, 249 lipid metabolic traits, and 10 lipid-lowering agents that were extracted from the largest genome-wide association study. Phenome-wide MR analyses were conducted to identify potential phenotypes associated with significant lipid-lowering agents.
Results: After multiple comparison adjustments (p < 0.0083), genetically proxied triglyceride (TG) (odds ratio [OR] 1.25, 95% confidence interval [CI] 1.07-1.47, p = 0.005) and high-density lipoprotein cholesterol (HDL-C) levels (OR 0.93, 95% CI 0.89-0.98, p = 0.008) showed causal relationships with the risk of IA. Four lipid metabolic traits showed a causal relationship with the risk of IA (p < 0.0002). As confirmed by drug target MR, the causal relationship between the HMGCR target and IA, HMGCR target and subarachnoid hemorrhage (SAH), ANGPTL3 target and SAH, CETP target, and SAH remained statistically significant after multiple adjustments (p < 0.005). Additionally, phenome-wide MR did not identify other diseases linked to the significant lipid-lowering agent (p < 6.39 × 10-5).
Discussion And Conclusion: This study not only supports that serum lipids (TG and HDL-C) are associated with IA but also confirms the positive effect and absence of safety concerns of intervening HMGCR, ANGPTL3, and CETP targets in IA and its subtypes, opening new avenues for IA treatment.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.