Genetic Association of Lipid-Lowering Drugs with Aortic Aneurysms: A Mendelian Randomization Study.

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: 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.

RESULTS: 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.

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