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Gene–Diet Interactions
Published in Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss, Nutrition and Cardiometabolic Health, 2017
Silvia Berciano, Jose M. Ordovas, Nathalie Bergeron, Patty W. Siri-Tarino, George A. Bray, Ronald M. Krauss
Some pioneering studies in the field of gene–diet interactions and cardiometabolic health relate to candidate genes in the path of lipoprotein metabolism, specifically associated with the APOE and the APOA1/APOC3/APOA4/APOA5 gene cluster. However, whereas there are clear and consistent associations between some of these loci and plasma lipid concentrations, the results from gene–diet interactions suffer from the similar lack of replication found for other metabolic pathways.
Gene-based therapy in lipid management: the winding road from promise to practice
Published in Expert Opinion on Investigational Drugs, 2020
Tycho R. Tromp, Erik S.G. Stroes, G. Kees Hovingh
In 2018, a meta-analysis comprising 137,895 individuals showed that in the 776 carriers of a LOF APOC3 allele, remnant cholesterol was 43% lower compared to non-carriers, while the mean LDL-C level was only slightly lower in carriers compared to controls (−4%, −0.1 mmol/L) [33]. Mediation analysis showed that the majority (37 of the observed 41%) of the observed beneficial effect on ischemic vascular disease risk in LOF carriers was attributable to the lower remnant cholesterol levels. Specifically, the apoB plasma level was 13% lower in heterozygous APOC3 LOF carriers compared to non-carriers, which is predicted to translate into significantly reduced CVD risk [21]. In light of the development of APOC3 gene-silencing therapies, it was particularly reassuring that homozygous carriers APOC3 LOF variants do not suffer from specific adverse phenotypes. In the Pakistani kindred in which the homozygous mutations were discovered, subjects were healthy and the only observed phenotype was a markedly blunted post-prandial triglyceride plasma level elevation [34]. This may indicate that aggressive lowering of apoC-III by gene therapy is safe. However, long-term clinical safety assessments are crucial to support this statement.
Experimental therapies targeting apolipoprotein C-III for the treatment of hyperlipidemia – spotlight on volanesorsen
Published in Expert Opinion on Investigational Drugs, 2019
Dimitrios Milonas, Konstantinos Tziomalos
In the circulation, APOC3 is mainly present in TRLs (chylomicrons and VLDL) and, to a lesser extent, in LDL and HDL particles [8]. Notably, the amount of APOC3 on HDL is high in the postabsorptive phase and low postprandially [8]. APOC3 is a key regulator of lipoprotein metabolism and plasma triglyceride levels. More specifically, it is known to inhibit LPL-mediated hydrolysis of TRLs and attenuate the uptake of TG-rich remnant lipoproteins by the liver [8,9]. At higher concentrations, APOC3 also inhibits the activity of hepatic lipase, an enzyme that plays an important role in the conversion of VLDL to intermediate-density lipoprotein (IDL) and LDL [10]. Thus, elevated levels of APOC3 in the plasma have been associated with impaired clearance of TRLs from the circulation resulting in the accumulation of atherogenic VLDL and chylomicron remnants in the circulation [11]. On the other hand, inhibition of LPL and hepatic lipase results in a decrease in LDL levels [8–11]. Besides its effect on lipoprotein metabolism, APOC3 has not only direct atherogenic properties by stimulating the adhesion of blood monocytes to endothelial cells and inducing the production of inflammatory mediators in these cells but also increases the binding of LDL to vascular proteoglycan, thereby enhancing LDL retention in the arterial wall [12].
Volanesorsen for treatment of familial chylomicronemia syndrome
Published in Expert Review of Cardiovascular Therapy, 2021
Julieta Lazarte, Robert A. Hegele
These genetic studies all pointed to the idea that interfering with apo C-III synthesis or secretion would reduce TG levels, which was theoretically beneficial to individuals with: 1) ASCVD residual risk due to mild-to-moderate HTG [37]; and 2) pancreatitis risk due to severe HTG, particularly those with FCS. Given the limited treatment options, risk to health and reduced quality of life in FCS, the development of a novel therapeutic approach that regulated APOC3 gene expression became a top priority.