Hou Yucheng, Zhao Jingwei, Xu Wanchuang, Chen Lei, Yang Jingyue, Wang Ziheng, Si Ke
Department of Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of General Surgery, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine & Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China.
Heliyon. 2024 Jul 3;10(13):e34089. doi: 10.1016/j.heliyon.2024.e34089. eCollection 2024 Jul 15.
Lipid metabolism plays an important role in the pathogenesis and development of calcific aortic valve stenosis. Our aim was to evaluate the causal effect of lipid-lowering drugs, such as low-density lipoprotein cholesterol (LDL-C) lowering and triglyceride lowering drugs, on the outcome of aortic valve stenosis using a two-sample Mendelian randomization (MR) study.
We used two genetic tools to represent the exposure of lipid-lowering drugs, including expression quantitative trait loci for the expression of drug target genes, and genetic variants within or near drug target genes that are associated with LDL-C and triglyceride concentrations from Genome-Wide Association Studies (GWAS). Effect estimates were calculated using summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis.
Based on the results of SMR and IVW-MR analysis, LDL-C-lowering PCSK9 inhibitors have potential in reducing the risk of aortic valve stenosis (for SMR, OR: 1.044; 95%CI: 1.002-1.404; = 0.047; for IVW-MR, OR: 1.647, 95%CI: 1.316-2.062, < 0.001). However, no significant association was observed between triglyceride target gene expression, as well as triglyceride-lowering drugs, and aortic valve stenosis.
This two-sample drug-targeted MR study suggests a potential causal relationship between PCSK9 inhibitors and the reduction of calcific aortic valve stenosis risk.
脂质代谢在钙化性主动脉瓣狭窄的发病机制和发展过程中起重要作用。我们的目的是使用两样本孟德尔随机化（MR）研究评估降脂药物，如降低低密度脂蛋白胆固醇（LDL-C）和降低甘油三酯的药物，对主动脉瓣狭窄结局的因果效应。
我们使用两种遗传工具来代表降脂药物的暴露情况，包括药物靶基因表达的表达数量性状位点，以及来自全基因组关联研究（GWAS）的与LDL-C和甘油三酯浓度相关的药物靶基因内部或附近的遗传变异。使用基于汇总数据的MR（SMR）和逆方差加权MR（IVW-MR）分析计算效应估计值。
基于SMR和IVW-MR分析结果，降低LDL-C的前蛋白转化酶枯草溶菌素9（PCSK9）抑制剂在降低主动脉瓣狭窄风险方面具有潜力（对于SMR，比值比：1.044；95%置信区间：从1.002至1.404；P = 0.047；对于IVW-MR，比值比：1.647，95%置信区间：1.316至2.062，P < 0.001）。然而，未观察到甘油三酯靶基因表达以及降低甘油三酯的药物与主动脉瓣狭窄之间存在显著关联。
这项两样本药物靶向MR研究表明PCSK9抑制剂与降低钙化性主动脉瓣狭窄风险之间存在潜在因果关系。
