The causal association between lipid-lowering strategies and risk of intracranial aneurysms: A drug-target Mendelian randomization study
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View abstract on PubMed
Summary
This summary is machine-generated.Higher proprotein convertase subtilisin/kexin type 9 (PCSK9) expression may reduce intracranial aneurysm (IA) risk. However, PCSK9 inhibitors, used to lower LDL-C, appear to increase IA development risk, warranting careful prescription.
Area Of Science
- Cardiovascular Research
- Genetics
- Neurology
Background
- Observational studies suggest a link between abnormal lipid profiles and intracranial aneurysms (IAs).
- Lipid-lowering therapies are hypothesized to potentially prevent IA progression and rupture.
Purpose Of The Study
- To investigate the causal effects of lipid-reducing strategies on the risk of developing intracranial aneurysms (IAs).
- To explore the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in IA development and rupture.
Main Methods
- Utilized Mendelian randomization (MR) with genetic variants as instrumental variables for lipid levels (LDL-C, HDL-C, triglycerides).
- Employed drug-target MR, two-sample MR (TSMR), and summary-data-based MR (SMR) using FinnGen Biobank GWAS data.
- Analyzed gene expression and protein levels to assess causal effects from transcriptional and translational perspectives.
Main Results
- PCSK9 inhibition-mediated reduction in LDL-C was associated with an increased risk of IA development (OR = 1.406).
- Higher PCSK9 expression showed protective effects against IA incidence (OR<sub>TSMR</sub> = 0.896, OR<sub>SMR</sub> = 0.881).
- PCSK9 demonstrated potential protective effects against IA rupture (OR<sub>TSMR</sub> = 0.893, OR<sub>SMR</sub> = 0.866).
Conclusions
- MR analyses suggest higher PCSK9 expression causally reduces the risk of IA formation and rupture.
- PCSK9 inhibitors may have a dual role, increasing IA development risk while PCSK9 itself is protective.
- Clinical use of PCSK9 inhibitors requires careful consideration in patients susceptible to IAs.
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