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

Laura Corbin, David A Hughes, Andrew J Chetwynd, Amy E Taylor, Andrew D Southam, Adrian Ratcliffe, Andris Jankevics, Ralf J M Weber, Alix Groom, Warwick B Dunn, Nicholas J Timpson

Research output: Contribution to journalArticle (Academic Journal)peer-review

3 Citations (Scopus)
66 Downloads (Pure)


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.
Original languageEnglish
Number of pages12
Volume(2020) 16
Issue number69
Publication statusPublished - 3 Jun 2020

Structured keywords

  • Brain and Behaviour
  • Tobacco and Alcohol


  • APOC3
  • triglyceride-rich lipoprotein
  • genotype
  • metabolites
  • recall-by-genotype


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