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<p>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 &lt; 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.</p>

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Association of genetically proxied cholesteryl ester transfer protein inhibition with risk of intracranial aneurysms: a Mendelian randomization study

  • 期刊论文

  • 发表日期：

    2026年7月28日

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  • Xialong Gu,
  • Xuebin Wen,
  • Lei Ma,
  • Dongfeng Wang,
  • Zhenqiang Li,
  • Maosong Chen,
  • Gengfan Ye

摘要

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.