The causal association between lipid-lowering strategies and risk of intracranial aneurysms: A drug-target Mendelian randomization study.

Abstract

Background: Observational studies have suggested potential correlations between unfavorable lipid profiles and the occurrence of intracranial aneurysms (IAs), proposing that lipid-lowering therapies might curb IA progression and prevent rupture. This study aimed to explore the causal impacts of lipid-reducing strategies on the risk of IAs.

Methods: We employed 3 genetic tools as proxies for our exposures and assessed causal effects using outcome genome-wide association study data from the FinnGen Biobank. Single nucleotide polymorphisms strongly associated with low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol, and triglycerides, located within ±100 kb of the region of target genes, were selected as instrumental variables for drug-target Mendelian randomization (MR). Additionally, gene expression and protein MR analyses were conducted to elucidate the causal effects of lipid levels from transcriptional and translational perspectives, using two-sample MR (TSMR) and summary-data-based MR (SMR).

Results: Drug-target MR analysis revealed that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition-mediated LDL-C reduction was associated with an increased risk of IA development (OR = 1.406, P = 3.28E-09). In contrast, protein MR demonstrated that higher PCSK9 expression had protective effects against IA incidence (OR_TSMR = 0.896, P = 1.79E-03; OR_SMR = 0.881, P = 1.78E-02). Subgroup analyses further suggested that PCSK9 might reduce the risk of IA rupture (OR_TSMR = 0.893, P = 1.08E-02; OR_SMR = 0.866, P = 3.39E-02).

Conclusion: Our MR analyses indicated a potential causal relationship between higher PCSK9 expression and a reduced risk of both IA formation and rupture, highlighting the dual role of PCSK9 inhibitors in cerebrovascular disease. Hence, careful consideration is warranted when prescribing PCSK9 inhibitors, particularly in patients at risk for developing IAs.