Mendelian randomisation finds higher genetically predicted CETP, alongside HMGCR and PCSK9, associated with greater aortic aneurysm risk (Eur J Prev Cardiol 2024)

Original title: Genetic association of lipid-lowering drugs with aortic aneurysms: a Mendelian randomization study

Eur J Prev Cardiol · 23 July 2024 · 5

Gao X, Luo W, Qu L, Yang M, Chen S, Lei L, Yan S, Liang H, Zhang X, Xiao M, Liao Y, Lee AP et al.

A drug-target Mendelian randomisation study used genome-wide association and expression quantitative trait loci data to test whether genetic proxies for lipid-lowering drugs are causally associated with aortic aneurysm (AA). Higher HMGCR expression was associated with increased AA risk (odds ratio 1.58, 95% CI, 1.20 to 2.09) and larger aortic lumen size. PCSK9 and CETP showed a suggestive relationship with AA risk (PCSK9: odds ratio 1.34, 95% CI, 1.10 to 1.63; CETP: odds ratio 1.38, 95% CI, 1.06 to 1.80), while NPC1L1 and LDLR showed no supporting evidence. The authors conclude higher gene expression of HMGCR, PCSK9 and CETP increases AA risk, implying inhibition of these targets, including CETP inhibition, may be protective, though the CETP association is described as suggestive rather than definitive.

Original abstract

Aims: The lack of effective pharmacotherapies for aortic aneurysms (AA) is a persistent clinical challenge. Lipid metabolism plays an essential role in AA. However, the impact of lipid-lowering drugs on AA remains controversial. The study aimed to investigate the genetic association between lipid-lowering drugs and AA.

Methods And Results: Our research used publicly available data on genome-wide association studies (GWASs) and expression quantitative trait loci (eQTL) studies. Genetic instruments, specifically eQTLs related to drug-target genes and SNPs (single nucleotide polymorphisms) located near or within the drug-target loci associated with low-density lipoprotein cholesterol (LDL-C), have been served as proxies for lipid-lowering medications. Drug-Target Mendelian Randomization (MR) study is used to determine the causal association between lipid-lowering drugs and different types of AA. The MR analysis revealed that higher expression of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase) was associated with increased risk of AA (OR = 1.58, 95% CI = 1.20-2.09, P = 1.20 × 10-03) and larger lumen size (aortic maximum area: OR = 1.28, 95% CI = 1.13-1.46, P = 1.48 × 10-04; aortic minimum area: OR = 1.26, 95% CI = 1.21-1.42, P = 1.78 × 10-04). PCSK9 (proprotein convertase subtilisin/kexin type 9) and CETP (cholesteryl ester transfer protein) show a suggestive relationship with AA (PCSK9: OR = 1.34, 95% CI = 1.10-1.63, P = 3.07 × 10-03; CETP: OR = 1.38, 95% CI = 1.06-1.80, P = 1.47 × 10-02). No evidence to support genetically mediated NPC1L1 (Niemann-Pick C1-Like 1) and LDLR (low-density lipoprotein cholesterol receptor) are associated with AA.

Conclusion: This study provides causal evidence for the genetic association between lipid-lowering drugs and AA. Higher gene expression of HMGCR, PCSK9, and CETP increases AA risk. Furthermore, HMGCR inhibitors may link with smaller aortic lumen size.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.