Background and Aims RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases. Methods RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank. Results In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [−0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (−0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60). Conclusions PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.

中文翻译：

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血管生成素样蛋白 3、脂质和心脏代谢风险的基因抑制

背景和目标 目前正在研究基于 RNA、抗体和基因组编辑的疗法，以确定抑制血管生成素样蛋白 3 (ANGPTL3) 是否可以降低脂蛋白脂质水平和动脉粥样硬化性心血管疾病 (ASCVD) 风险。孟德尔随机化 (MR) 用于确定影响 ANGPTL3 肝脏基因表达、血液水平和蛋白质结构的遗传变异是否会影响甘油三酯和载脂蛋白 B (apoB) 水平以及冠状动脉疾病 (CAD)、缺血性中风 (IS)和其他心脏代谢疾病。方法对 246 个外植肝脏样本进行 RNA 测序和全基因组基因分型，以确定与 ANGPTL3 肝脏表达相关的单核苷酸多态性 (SNP)。使用来自 deCODE 研究 (n = 35 359) 的 ANGPTL3 血浆蛋白水平的全基因组汇总统计数据。英国生物银行共鉴定出 647 名与较低血浆甘油三酯水平相关的 ANGPTL3 蛋白截短变体 (PTV) 携带者。使用影响 ANGPTL3 肝脏表达或 ANGPTL3 血浆蛋白水平的 SNP 作为暴露和心脏代谢疾病作为结果（CAD、IS、心力衰竭、非酒精性脂肪肝、急性胰腺炎和 2 型糖尿病）进行两样本 MR。英国生物银行还研究了影响血浆甘油三酯水平的罕见 PTV 对 apoB 水平和 CAD 的影响。结果 在双样本 MR 研究中，影响 ANGPTL3 肝脏或血液表达水平的常见遗传变异对血浆甘油三酯水平有很强的影响，对低密度脂蛋白胆固醇的影响较小，对 apoB 水平的影响较弱，并且没有影响。对 CAD 或其他心脏代谢疾病的影响。在英国生物银行中，罕见 ANGPTL3 PTV 的携带者可终生降低中位血浆甘油三酯水平 [−0.37（四分位距 0.41）mmol/L]，其 apoB 水平略低（−0.06 ± 0.32 g/L），并且 CAD 事件发生率相似与非携带者相比（携带者与非携带者为 10.2% vs. 10.9%，P = .60）。结论 影响 ANGPTL3 蛋白结构的 PTV 以及影响 ANGPTL3 肝表达和/或血液蛋白水平的常见遗传变异对循环血浆甘油三酯水平有很强的影响，对循环 apoB 水平影响较弱，对 ASCVD 没有影响。对于 apoB 水平非常升高的患者，可能需要近乎完全抑制 ANGPTL3 功能才能降低 ASCVD 风险。