Introduction

High plasma triacylglyceride levels are known to be associated with increased risk of atherosclerotic cardiovascular disease. Apolipoprotein C-III (apoC-III) is a key regulator of plasma triacylglyceride levels and is associated with hypertriglyceridemia via a number of pathways. There is consistent evidence for an association of cardiovascular events with blood apoC-III level, with support from human genetic studies of APOC3 variants. As such, apoC-III has been recognised as a potential therapeutic target for patients with severe hypertriglyceridaemia with one of the most promising apoC-III-targeting drugs, volanesorsen, having recently progressed through Phase III trials.

Objectives

To exploit a rare loss of function variant in APOC3 (rs138326449) to characterise the potential long-term treatment effects of apoC-III targeting interventions on the metabolome.

Methods

In a recall-by-genotype study, 115 plasma samples were analysed by UHPLC-MS to acquire non-targeted metabolomics data. The study included samples from 57 adolescents and 33 adults. Overall, 12 985 metabolic features were tested for an association with APOC3 genotype.

Results

161 uniquely annotated metabolites were found to be associated with rs138326449(APOC3). The highest proportion of associated metabolites belonged to the acyl-acyl glycerophospholipid and triacylglyceride metabolite classes. In addition to the anticipated (on-target) reduction of metabolites in the triacylglyceride and related classes, carriers of the rare variant exhibited previously unreported increases in levels of a number of metabolites from the acyl-alkyl glycerophospholipid class.

Conclusion

Overall, our results suggest that therapies targeting apoC-III may potentially achieve a broad shift in lipid profile that favours better metabolic health.

中文翻译：

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通过基因型的基于样本的回忆对 APOC3/富含甘油三酯的脂蛋白途径中的紊乱进行代谢表征。

介绍

已知高血浆甘油三酯水平与动脉粥样硬化性心血管疾病风险增加有关。载脂蛋白 C-III (apoC-III) 是血浆甘油三酯水平的关键调节剂，并通过多种途径与高甘油三酯血症相关。有一致的证据表明心血管事件与血液 apoC-III 水平相关，并得到APOC3变体的人类遗传学研究的支持。因此，apoC-III 已被认为是严重高甘油三酯血症患者的潜在治疗靶点，其中最有希望的 apoC-III 靶向药物之一 volanesorsen 最近已通过 III 期试验取得进展。

目标

利用APOC3 (rs138326449) 中罕见的功能丧失变异体来表征 apoC-III 靶向干预对代谢组的潜在长期治疗效果。

方法

在一项按基因型召回的研究中，通过 UHPLC-MS 分析了 115 个血浆样本，以获取非靶向代谢组学数据。该研究包括来自 57 名青少年和 33 名成人的样本。总体而言，测试了 12 985 个代谢特征与APOC3基因型的关联。

结果

发现 161 种独特注释的代谢物与 rs138326449（APOC3）相关。最高比例的相关代谢物属于酰基-酰基甘油磷脂和甘油三酯代谢物类别。除了三酰基甘油酯和相关类别中代谢物的预期（靶向）减少外，这种罕见变体的携带者还表现出以前未报道的来自酰基-烷基甘油磷脂类的一些代谢物水平的增加。

结论

总体而言，我们的结果表明，靶向 apoC-III 的疗法可能会实现脂质谱的广泛转变，从而有利于更好的代谢健康。