Inhibitors of apolipoprotein C-III (apoC3) are currently approved for the reduction of triglyceride levels in patients with Familial Chylomicronemia Syndrome. We used drug target Mendelian randomization (MR) to assess the effect of genetically predicted decrease in apoC3 blood protein levels on cardiometabolic traits and diseases. We quantified lifelong reductions in apoC3 blood levels by selecting all genome wide significant and independent (<0.1) single nucleotide polymorphisms (SNPs) in the gene region ±1 Mb, from three genome-wide association studies (GWAS) of apoC3 blood protein levels (deCODE, n = 35,378, Fenland, n = 10,708 and ARIC, n = 7213). We included the largest GWASes on 18 cardiometabolic traits and 9 cardiometabolic diseases as study outcomes. A one standard deviation lowering in apoC3 blood protein levels was associated with lower triglycerides, apolipoprotein B, low-density lipoprotein cholesterol, alanine aminotransferase, and glomerular filtration rate as well as higher high-density lipoprotein cholesterol levels. ApoC3 lowering was also associated with lower risk of acute pancreatitis (odds ratio [OR] = 0.91 95% CI = 0.82 to 1.00), aortic stenosis (OR = 0.82 95% CI = 0.73 to 0.93), and coronary artery disease (OR = 0.86 95% CI = 0.80 to 0.93), and was associated with increased parental lifespan (0.06 95% CI = 0.03–0.09 years). These results were concordant across robust MR methods, the three protein datasets and upon adjustment for APOA1, APOA4 and APOA5 using a multivariable MR framework. These results provide evidence that apoC3 lowering could result in widespread benefits for cardiometabolic health and encourage the launch of trials on apoC3 inhibition for coronary artery disease prevention.

中文翻译：

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药物靶标孟德尔随机化支持降低载脂蛋白 C3，以降低脂蛋白脂质水平和预防心血管疾病

载脂蛋白 C-III (apoC3) 抑制剂目前被批准用于降低家族性乳糜微粒血症综合征患者的甘油三酯水平。我们使用药物靶标孟德尔随机化 (MR) 来评估基因预测的 apoC3 血液蛋白水平下降对心脏代谢特征和疾病的影响。我们通过从三项 apoC3 血液蛋白水平的全基因组关联研究 (GWAS) 中选择 ±1 Mb 基因区域中所有全基因组范围内显着且独立 (<0.1) 的单核苷酸多态性 (SNP) 来量化 apoC3 血液水平的终生降低情况（解码，n = 35,378，Fenland，n = 10,708 和 ARIC，n = 7213）。我们将 18 种心脏代谢特征和 9 种心脏代谢疾病的最大 GWAS 纳入研究结果。 apoC3 血液蛋白水平降低 1 个标准差与甘油三酯、载脂蛋白 B、低密度脂蛋白胆固醇、丙氨酸转氨酶和肾小球滤过率降低以及高密度脂蛋白胆固醇水平降低相关。 ApoC3 降低还与急性胰腺炎（比值比 [OR] = 0.91 95% CI = 0.82 至 1.00）、主动脉瓣狭窄（OR = 0.82 95% CI = 0.73 至 0.93）和冠状动脉疾病（OR = 0.86 95% CI = 0.80 至 0.93），并且与父母寿命延长相关（0.06 95% CI = 0.03–0.09 年）。这些结果在稳健的 MR 方法、三个蛋白质数据集以及使用多变量 MR 框架对 APOA1、APOA4 和 APOA5 进行调整后是一致的。这些结果提供证据表明，apoC3 降低可能对心脏代谢健康产生广泛的益处，并鼓励开展抑制 apoC3 预防冠状动脉疾病的试验。