■前蛋白转化酶枯草杆菌蛋白酶/kexin9型(PCSK9),3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR),胆固醇酯转运蛋白(CETP)和载脂蛋白C3(APOC3)是脂质代谢的关键调节因子,针对这些基因的许可药物。通过抑制这些基因使用降脂治疗已经证明了心血管疾病风险的降低。然而,关于它们对主动脉疾病和钙化性主动脉瓣疾病(CAVS)的潜在长期影响的担忧仍然存在.这项研究旨在调查类似这些基因的遗传变异与主动脉疾病之间的因果关系。以及使用孟德尔随机化(MR)的钙化主动脉瓣疾病。
■我们采用低密度脂蛋白胆固醇(LDL-C)的汇总统计量进行药物靶向孟德尔随机化,以替代PCSK9,HMGCR,CETP和APOC3。随后,我们研究了药物靶标遗传变异与钙化性主动脉瓣狭窄和主动脉疾病之间的关联,包括胸主动脉瘤(TAA),腹主动脉瘤(AAA),和主动脉夹层(AD)。
■模仿较低LDL-C水平的基因构建变体与冠状动脉疾病风险降低相关,验证其可靠性。值得注意的是,HMGCR抑制对TAA表现出强大的保护作用(比值比(OR):0.556,95%CI:0.372-0.831,p=0.004),AAA(OR:0.202,95%CI:0.107-0.315,p=4.84×10-15),和AD(OR:0.217,95%CI:0.098-0.480,p=0.0002)。同样,PCSK9,CETP和APOC3抑制因子降低了AAA的风险(OR:0.595,95%CI:0.485-0.730,p=6.75×10-7,OR:0.127,95%CI:0.066-0.243,p=4.42×10-10和OR:0.387,95%CI:0.182-0.824,p=0.014),同时对TAA和TAA显示中性影响。抑制HMGCR,PCSK9和APOC3在预防CAVS方面显示出有希望的潜力,比值比为0.554(OR:0.554,95%CI:0.433-0.707,p=2.27×10-6),0.717(95%CI:0.635-0.810,p=9.28×10-8),和0.540(95%CI:0.351-0.829,p=0.005),分别。然而,CETP抑制在预防CAVS方面未显示任何显著益处(95%CI:0.704-1.544,p=0.836)。这些发现在各种孟德尔随机化方法中的一致性,考虑到关于遗传多效性的不同假设,增强了因果推断。
■我们的MR分析显示,类似他汀类药物的遗传变异与AAA风险降低有关,TAA,AD和CAVS。HMGCR,PCSK9和APOC3抑制剂而不是CETP抑制剂具有降低CAVS的积极益处。值得注意的是,PCSK9、CETP和APOC3抑制剂表现出保护性作用,主要针对AAA,没有明显的好处延伸到TAA或AD。
UNASSIGNED: 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).
UNASSIGNED: 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).
UNASSIGNED: 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 × 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 × 10-7, OR: 0.127, 95% CI: 0.066-0.243, p = 4.42 × 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 × 10-6), 0.717 (95% CI: 0.635-0.810, p = 9.28 × 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.
UNASSIGNED: 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.