Causal Relationships between Lipid-Lowering Drug Target and Aortic Disease and Calcific Aortic Valve Stenosis: A Two-Sample Mendelian Randomization.

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), cholesteryl ester transfer protein (CETP) and apolipoprotein C3 (APOC3) are pivotal regulators of lipid metabolism, with licensed drugs targeting these genes. The use of lipid-lowering therapy via the inhibition of these genes has demonstrated a reduction in the risk of cardiovascular disease. However, concerns persist regarding their potential long-term impact on aortic diseases and calcific aortic valve disease (CAVS). This study aims to investigate causal relationships between genetic variants resembling these genes and aortic disease, as well as calcific aortic valve disease using Mendelian randomization (MR).

Methods: We conducted drug-target Mendelian randomization employing summary-level statistics of low-density lipoprotein cholesterol (LDL-C) to proxy the loss-of-function of PCSK9, HMGCR, CETP and APOC3. Subsequently, we investigated the association between drug-target genetic variants and calcific aortic valve stenosis and aortic diseases, including thoracic aortic aneurysm (TAA), abdominal aortic aneurysm (AAA), and aortic dissection (AD).

Results: The genetically constructed variants mimicking lower LDL-C levels were associated with a decreased risk of coronary artery disease, validating their reliability. Notably, HMGCR inhibition exhibited a robust protective effect against TAA (odds ratio (OR): 0.556, 95% CI: 0.372-0.831, p = 0.004), AAA (OR: 0.202, 95% CI: 0.107-0.315, p = 4.84 $\times$ 10^-15), and AD (OR: 0.217, 95% CI: 0.098-0.480, p = 0.0002). Similarly, PCSK9, CETP and APOC3 inhibition proxies reduced the risk of AAA (OR: 0.595, 95% CI: 0.485-0.730, p = 6.75 $\times$ 10^-7, OR: 0.127, 95% CI: 0.066-0.243, p = 4.42 $\times$ 10^-10, and OR: 0.387, 95% CI: 0.182-0.824, p = 0.014, respectively) while showing a neutral impact on TAA and AD. Inhibition of HMGCR, PCSK9, and APOC3 showed promising potential in preventing CAVS with odds ratios of 0.554 (OR: 0.554, 95% CI: 0.433-0.707, p = 2.27 $\times$ 10^-6), 0.717 (95% CI: 0.635-0.810, p = 9.28 $\times$ 10^-8), and 0.540 (95% CI: 0.351-0.829, p = 0.005), respectively. However, CETP inhibition did not demonstrate any significant benefits in preventing CAVS (95% CI: 0.704-1.544, p = 0.836). The consistency of these findings across various Mendelian randomization methods, accounting for different assumptions concerning genetic pleiotropy, enhances the causal inference.

Conclusions: Our MR analysis reveals that genetic variants resembling statin administration are associated with a reduced risk of AAA, TAA, AD and CAVS. HMGCR, PCSK9 and APOC3 inhibitors but not CETP inhibitors have positive benefits of reduced CAVS. Notably, PCSK9, CETP and APOC3 inhibitors exhibit a protective impact, primarily against AAA, with no discernible benefits extending to TAA or AD.