Metabolic characterisation of disturbances in the APOC3/triglyceride-rich lipoprotein pathway through sample-based recall by genotype

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: 144 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 and ceramide classes. CONCLUSION: Overall, our results suggest that therapies targeting apoC-III may potentially achieve a broad shift in lipid profile that favours better metabolic health. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11306-020-01689-9) contains supplementary material, which is available to authorized users.