Gagnon Eloi, Gill Dipender, Bourgault Jérôme, Gobeil Émilie, Mitchell Patricia L, Girard Arnaud, Paulin Audrey, Couture Christian, Bossé Yohan, Thériault Sébastien, Mathieu Patrick, Vohl Marie-Claude, Tchernof André, Ray Kausik K, Kastelein John J P, Arsenault Benoit J
Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Y-3106, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Québec, QC, Canada G1V 4G5.
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Cardiovasc Res. 2025 Jul 8;121(7):1066-1075. doi: 10.1093/cvr/cvaf078.
RNA interference therapies targeting liver expression of the gene proprotein convertase subtilisin/kexin type 9 (PCSK9) lower LDL-cholesterol (LDL-C) and apolipoprotein B (apoB) levels. As opposed to monoclonal antibodies, which neutralise PCSK9 circulating protein, their effect on atherosclerotic cardiovascular disease (ASCVD) outcomes is unknown. We used genetic variants in the PCSK9 locus influencing PCSK9 function or gene expression in the liver to determine whether antibodies against PCSK9 and RNA interference therapies could have comparable effects on ASCVD.
We performed genome-wide genotyping and RNA sequencing of 504 human liver sample and identified a genetic variant (rs472495) explaining 5.6% of liver PCSK9 gene expression to mimic lifelong RNA interference of PCSK9. We used the PCSK9 R46L variant, known to alter PCSK9 function, to model antibody-based PCSK9 inhibition. For each standard deviation decrease in apoB levels, both variants were similarly associated with coronary artery disease risk: (odds ratio [OR] = 0.40, 95% confidence interval [CI]: 0.31-0.51, P = 3.7e-13 for rs472495 which affects liver PCSK9 expression) and (OR = 0.48, 95% CI: 0.43-0.55, P = 1.3e-28 for R46L which affects protein levels). Comparable effects of these two genetic inhibition approaches were observed for aortic stenosis, heart failure, ischemic stroke, Type 2 diabetes and glycemic traits as well as non-alcoholic fatty liver disease and liver enzymes.
For a given reduction in apoB levels, genetically predicted reductions in PCSK9 function (mimicking PCSK9 neutralizing antibodies) and liver PCSK9 gene expression levels (mimicking PCSK9 RNA interference) were comparably associated with a lower risk of coronary artery disease. These genetic data suggest that LDL-C/apoB reductions may provide cardiovascular benefits, regardless of how PCSK9 function is inhibited.
靶向肝脏中前蛋白转化酶枯草溶菌素/九型凯新蛋白酶（PCSK9）基因表达的RNA干扰疗法可降低低密度脂蛋白胆固醇（LDL-C）和载脂蛋白B（apoB）水平。与中和循环中PCSK9蛋白的单克隆抗体不同，其对动脉粥样硬化性心血管疾病（ASCVD）结局的影响尚不清楚。我们利用PCSK9基因座中影响PCSK9功能或肝脏基因表达的遗传变异，来确定抗PCSK9抗体和RNA干扰疗法对ASCVD是否可能有相似的作用。
我们对504份人类肝脏样本进行了全基因组基因分型和RNA测序，鉴定出一个遗传变异（rs472495），该变异可解释肝脏PCSK9基因表达的5.6%，以模拟PCSK9的终身RNA干扰。我们使用已知会改变PCSK9功能的PCSK9 R46L变异，来模拟基于抗体的PCSK9抑制作用。apoB水平每降低一个标准差，两种变异与冠状动脉疾病风险的关联相似：（比值比[OR]=0.40，95%置信区间[CI]：0.31 - 0.51，影响肝脏PCSK9表达的rs472495的P = 3.7e - 13）以及（OR = 0.48，95%CI：0.43 - 0.55，影响蛋白水平的R46L的P = 1.3e - 28）。在主动脉瓣狭窄、心力衰竭、缺血性中风、2型糖尿病和血糖特征以及非酒精性脂肪性肝病和肝酶方面，也观察到这两种基因抑制方法的类似效果。
对于apoB水平的给定降低，基因预测的PCSK9功能降低（模拟PCSK9中和抗体）和肝脏PCSK9基因表达水平降低（模拟PCSK9 RNA干扰）与较低的冠状动脉疾病风险具有相似的关联。这些基因数据表明，无论PCSK9功能如何被抑制，LDL-C/apoB的降低都可能带来心血管益处。
