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Association of genetically proxied cholesteryl ester transfer protein inhibition with risk of intracranial aneurysms:
Xialong Gu1, Xuebin Wen2, Lei Ma1
1Department of Neurosurgery, The Affiliated Lihuili Hospital of Ningbo University, Ningbo 315040, Zhejiang, China.
Background:
Lipid-lowering drugs have been implicated in aneurysm pathophysiology, but whether genetically proxied Cholesteryl Ester Transfer Protein (CETP) inhibition is associated with intracranial aneurysms (IA) and their clinical subtypes remains unclear. This study used drug-target Mendelian randomization to investigate the potential association between genetically proxied CETP inhibition and the risks of IA, subarachnoid hemorrhage (SAH), and unruptured IA (UIA).
Methods:
We performed Mendelian randomization (MR) analyses to evaluate the associations of CETP inhibition with risks for IA, SAH and UIA.
Results:
SMR analyses provided suggestive evidence that lower CETP expression in whole blood was associated with lower risks of IA (odds ratio [OR] = 0.715, 95% confidence interval [CI] = 0.520-0.984; PSMR = 3.95E-02; PHEIDI = 0.229) and SAH (OR = 0.655, 95% CI = 0.454-0.945; PSMR = 2.36E-02; PHEIDI = 0.459). IVW-MR analyses also yielded suggestive associations for IA (OR = 0.645, 95% CI = 0.440-0.945; p = 0.025) and SAH (OR = 0.643, 95% CI = 0.437-0.946; p = 0.025), which were directionally consistent with the SMR estimates. No association was observed for UIA. After multiplicity correction across the three aneurysm outcomes (Bonferroni-corrected threshold p < 0.017 or Benjamini-Hochberg FDR), the associations remained nominal rather than stringent and should therefore be interpreted as suggestive.
Conclusion:
This study provides suggestive genetic evidence consistent with a potential protective association of CETP inhibition with IA rupture and subsequent SAH. Given the borderline statistical significance and the translational limitations of MR-derived estimates, these findings should be regarded as hypothesis-generating and require validation in dedicated pharmacoepidemiological or clinical studies.
Insights
Genetically proxied Cholesteryl Ester Transfer Protein (CETP) inhibition may offer protection against intracranial aneurysms (IA) and subarachnoid hemorrhage (SAH). Further research is needed to confirm these findings in clinical settings.
Area of Science:
- Genetics
- Cardiovascular Science
- Pharmacology
Background:
- Lipid-lowering drugs are linked to aneurysm development.
- The role of Cholesteryl Ester Transfer Protein (CETP) inhibition in intracranial aneurysms (IA) is not fully understood.
Purpose of the Study:
- To investigate the association between genetically proxied CETP inhibition and the risks of IA, subarachnoid hemorrhage (SAH), and unruptured IA (UIA).
Main Methods:
- Utilized drug-target Mendelian randomization (MR) analyses.
- Evaluated associations of CETP inhibition with risks for IA, SAH, and UIA.
Main Results:
- Suggestive evidence indicated lower CETP expression was linked to reduced risks of IA and SAH.
- Associations remained nominal after multiplicity correction, suggesting a potential protective effect.
Conclusions:
- Suggestive genetic evidence supports a potential protective role of CETP inhibition against IA rupture and SAH.
- Findings are hypothesis-generating and require validation through pharmacoepidemiological or clinical studies.
