Liang Yang, Mingyuan Xu, Xixi Gao, Jingwen Liu, Dingkai Zhang, Zhaohua Zhang, Zhidong Ye, Jianyan Wen, Peng Liu
{"title":"Causal Relationships between Lipid-Lowering Drug Target and Aortic Disease and Calcific Aortic Valve Stenosis: A Two-Sample Mendelian Randomization.","authors":"Liang Yang, Mingyuan Xu, Xixi Gao, Jingwen Liu, Dingkai Zhang, Zhaohua Zhang, Zhidong Ye, Jianyan Wen, Peng Liu","doi":"10.31083/j.rcm2508292","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Proprotein convertase subtilisin/kexin type 9 (<i>PCSK9</i>), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (<i>HMGCR</i>), cholesteryl ester transfer protein (<i>CETP</i>) and apolipoprotein C3 (<i>APOC3</i>) 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).</p><p><strong>Methods: </strong>We conducted drug-target Mendelian randomization employing summary-level statistics of low-density lipoprotein cholesterol (LDL-C) to proxy the loss-of-function of <i>PCSK9</i>, <i>HMGCR</i>, <i>CETP</i> and <i>APOC3</i>. 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).</p><p><strong>Results: </strong>The genetically constructed variants mimicking lower LDL-C levels were associated with a decreased risk of coronary artery disease, validating their reliability. Notably, <i>HMGCR</i> inhibition exhibited a robust protective effect against TAA (odds ratio (OR): 0.556, 95% CI: 0.372-0.831, <i>p</i> = 0.004), AAA (OR: 0.202, 95% CI: 0.107-0.315, <i>p</i> = 4.84 <math><mo>×</mo></math> 10<sup>-15</sup>), and AD (OR: 0.217, 95% CI: 0.098-0.480, <i>p</i> = 0.0002). Similarly, <i>PCSK9</i>, <i>CETP</i> and <i>APOC3</i> inhibition proxies reduced the risk of AAA (OR: 0.595, 95% CI: 0.485-0.730, <i>p</i> = 6.75 <math><mo>×</mo></math> 10<sup>-7</sup>, OR: 0.127, 95% CI: 0.066-0.243, <i>p</i> = 4.42 <math><mo>×</mo></math> 10<sup>-10</sup>, and OR: 0.387, 95% CI: 0.182-0.824, <i>p</i> = 0.014, respectively) while showing a neutral impact on TAA and AD. Inhibition of <i>HMGCR</i>, <i>PCSK9</i>, and <i>APOC3</i> showed promising potential in preventing CAVS with odds ratios of 0.554 (OR: 0.554, 95% CI: 0.433-0.707, <i>p</i> = 2.27 <math><mo>×</mo></math> 10<sup>-6</sup>), 0.717 (95% CI: 0.635-0.810, <i>p</i> = 9.28 <math><mo>×</mo></math> 10<sup>-8</sup>), and 0.540 (95% CI: 0.351-0.829, <i>p</i> = 0.005), respectively. However, <i>CETP</i> inhibition did not demonstrate any significant benefits in preventing CAVS (95% CI: 0.704-1.544, <i>p</i> = 0.836). The consistency of these findings across various Mendelian randomization methods, accounting for different assumptions concerning genetic pleiotropy, enhances the causal inference.</p><p><strong>Conclusions: </strong>Our MR analysis reveals that genetic variants resembling statin administration are associated with a reduced risk of AAA, TAA, AD and CAVS. <i>HMGCR</i>, <i>PCSK9</i> and <i>APOC3</i> inhibitors but not <i>CETP</i> inhibitors have positive benefits of reduced CAVS. Notably, <i>PCSK9</i>, <i>CETP</i> and <i>APOC3</i> inhibitors exhibit a protective impact, primarily against AAA, with no discernible benefits extending to TAA or AD.</p>","PeriodicalId":20989,"journal":{"name":"Reviews in cardiovascular medicine","volume":"25 8","pages":"292"},"PeriodicalIF":1.9000,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11367000/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Reviews in cardiovascular medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.31083/j.rcm2508292","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0
Abstract
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 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.
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.
期刊介绍:
RCM is an international, peer-reviewed, open access journal. RCM publishes research articles, review papers and short communications on cardiovascular medicine as well as research on cardiovascular disease. We aim to provide a forum for publishing papers which explore the pathogenesis and promote the progression of cardiac and vascular diseases. We also seek to establish an interdisciplinary platform, focusing on translational issues, to facilitate the advancement of research, clinical treatment and diagnostic procedures. Heart surgery, cardiovascular imaging, risk factors and various clinical cardiac & vascular research will be considered.