Genetics
Mendelian randomisation study centred on HMGCR also finds CETP-mediated LDL-C consistently associated with lower aortic aneurysm risk (Nutr Metab 2024)
Original title: HMGCR as a promising molecular target for therapeutic intervention in aortic aneurisms: a mendelian randomization study
A Mendelian randomisation study assessed the causal impact of six LDL-C-lowering drug targets (HMGCR, PCSK9, NPC1L1, CETP, APOB, LDLR) on aortic, thoracic, abdominal and cerebral aneurysms, using expression quantitative trait loci and genetic variants as drug-target proxies across summary-data-based, inverse-variance-weighted and multivariable MR methods. The primary finding was that higher HMGCR expression and HMGCR-mediated LDL-C were associated with increased risk of aortic, thoracic, abdominal and cerebral aneurysms. Consistent positive associations, in the protective direction, were also observed for PCSK9 and CETP genes and PCSK9-mediated and CETP-mediated LDL-C levels with aortic aneurysm and abdominal aortic aneurysm risk, robust to adjustment for BMI, smoking and hypertension. APOB, NPC1L1 and LDLR showed no consistent association with aneurysm subtypes. The headline conclusion of this paper concerns HMGCR as a novel aneurysm drug target; CETP appears as a secondary, consistent but unquantified positive signal.
Original abstract
Background: Despite the exploration of the connections between serum low-density lipoprotein cholesterol (LDL-C) levels and aneurisms in epidemiological studies, causality remains unclear. Therefore, this study aimed to assess the causal impact of LDL-C-lowering targets (HMGCR, PCSK9, NPC1L1, CETP, APOB, and LDLR) on various forms of aneurisms using Mendelian Randomization (MR) analysis.
Methods: Two genetic instruments acted as proxies for exposure to LDL-C-lowering drugs: expression quantitative trait loci of drug target genes and genetic variants linked to LDL-C near drug target genes. Summary-data-based MR (SMR), inverse-variance-weighted MR (IVW-MR), and multivariable MR (MVMR) methods were employed to compute the effect estimates.
Results: The SMR analysis revealed substantial associations between increased HMGCR expression and a heightened risk of aortic aneurism (odds ratio [OR] = 1.603, 95% confidence interval [CI] = 1.209-2.124), thoracic aortic aneurism (OR = 1.666, 95% CI = 1.122-2.475), and abdominal aortic aneurism (OR = 1.910, 95% CI = 1.278-2.856). Likewise, IVW-MR analysis demonstrated positive correlations between HMGCR-mediated LDL-C and aortic aneurism (OR = 2.228, 95% CI = 1.702-2.918), thoracic aortic aneurism (OR = 1.751, 95% CI = 1.191-2.575), abdominal aortic aneurism (OR = 4.784, 95% CI = 3.257-7.028), and cerebral aneurism (OR = 1.993, 95% CI = 1.277-3.110). Furthermore, in the MVMR analysis, accounting for body mass index, smoking, and hypertension, a significant positive relationship was established between HMGCR-mediated LDL-C levels and the development of aortic aneurisms, encompassing both thoracic and abdominal subtypes. Similarly, consistent positive associations were observed for PCSK9 and CETP genes, as well as PCSK9-mediated and CETP-mediated LDL-C levels, with the occurrence of aortic aneurism and abdominal aortic aneurism. Nonetheless, the evidence for potential associations between APOB, NPC1L1 and LDLR with specific subtypes of aortic aneurisms lacked consistent support from both SMR and IVW-MR analyses.
Conclusions: Our MR analysis offered compelling evidence of a plausible causal link between HMGCR and an increased risk of aortic aneurism, encompassing both thoracic and abdominal types. These groundbreaking findings further bolster the case for the deployment of HMGCR inhibitors in the treatment of aortic aneurisms, including both thoracic and abdominal variants.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.