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

Abstract

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-IIItargeting 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.

Balancing scientific interests and the rights of participants in designing a recall by genotype study

“…RbG studies are often conducted as sub-studies within the framework of a larger-scale research study, which can be longitudinal, long term, biobank based, and with broad aims. The most recently published RbG studies included in our literature review were conducted in Europe, mostly in the frame of population studies such as the Cambridge BioResource [25,26], the Avon Longitudinal Study of Parents and Children [27,28], the Exeter 10000 study [29], the Estonian Biobank of the Estonian Genome Center [30], the PPP-Botnia study [31], and other types of study [32,33]. These RbG studies were designed to understand a variety of diseases, conditions, and topics, such as inflammatory bowel disease [25], arterial and venous diseases [26], schizophrenia [27], cardiovascular disease [28], level of adiponectin [29], familial hypercholesterolaemia [30], type 2 diabetes [31], anxiety disorders [32], and predisposition to hypertriacylglycerolaemia [33].…”

“…The most recently published RbG studies included in our literature review were conducted in Europe, mostly in the frame of population studies such as the Cambridge BioResource [25,26], the Avon Longitudinal Study of Parents and Children [27,28], the Exeter 10000 study [29], the Estonian Biobank of the Estonian Genome Center [30], the PPP-Botnia study [31], and other types of study [32,33]. These RbG studies were designed to understand a variety of diseases, conditions, and topics, such as inflammatory bowel disease [25], arterial and venous diseases [26], schizophrenia [27], cardiovascular disease [28], level of adiponectin [29], familial hypercholesterolaemia [30], type 2 diabetes [31], anxiety disorders [32], and predisposition to hypertriacylglycerolaemia [33]. Where the variant(s) under study had clinical implications and treatment options for the participant and their relatives, genetic counselling, the disclosure of the carrier status, and further tests for family members were offered [30].…”

Triglyceride and Triglyceride-Rich Lipoproteins in Atherosclerosis

“…Volanesorsen is an antisense oligonucleotide targeting apoCIII mRNA, and it is developed for treatment of familial CM syndrome (FCS), HTG, and familial partial lipodystrophy ( Gouni-Berthold, 2017 ; Paik and Duggan, 2019 ). Based on the beneficial effects observed in the phase III study, volanesorsen was approved in the European Union for treatment of adult FCS patients in May 2019 ( Hegele et al, 2018 ; Corbin et al, 2020 ; Gouni-Berthold et al, 2021 ; Lazarte and Hegele, 2021 ). The average TG level in FCS patients decreases by 77% after treatment using volanesorsen (300 mg) once a week for 3 months ( Witztum et al, 2019 ).…”