Genetic evidence for a causal role for triglycerides in CV diseaseBudoff M. AM J Cardiol. 2016
Triglycerides and Triglyceride-rich Lipoproteins in the Causal Pathway of Cardiovascular Disease
The American Journal of Cardiology (2016) doi: 10.1016/j.amjcard.2016.04.004
Epidemiological and clinical data have pointed at elevated triglyceride (TG) levels as a biomarker of CV risk. Evidence is now accumulating that TGs and TG-rich lipoproteins (TRLs) are causally involved in the pathogenesis of atherosclerotic CV disease (ASCVD). This article gives an overview of TRL metabolism, and summarises the evidence supporting a causal role of TGs and TRLs in ASCVD, and how this data can affect management of patients with dyslipidaemia.
Overview of TRL metabolismLDL stimulates hydrolysis of the core TGs in the TRLs VLDL and chylomicrons. This produces VLDL remnants and chylomicron remnants, which are enriched in cholesterol relative to TGs. Some particles are not cleared but remain in the circulation, and are further modified to form cholesterol-enriched LDL particles.
Remnant cholesterol content can be calculated by subtracting LDL-c from non-HDL-c level. VLDL remnants and chylomicron remnants can be taken up by macrophages in the arterial wall. They may contribute to vascular inflammation and atherosclerotic plaque development and progression, without the need for oxidative modification as is required for LDL particles.
Full activation of LPL needs cofactor ApoC-II, and ApoA-V seems to enhance LPL activity. On the other hand, ApoC-III inhibits LPL and may be involved in hepatic VLDL assembly and secretion.
TRL metabolism and TG levels are further influenced by ANGPTL3 and 4, both by the secreted protein products and by genetic alterations in these factors.
Genetic evidence for TGs and TRLs in the causal pathway of ASCVDGenetic data can help elucidate causal relationships between lipid biomarkers and disease.
Mutational analyses/exome sequencingSeveral mutation in the LPL gene have been identified that reduce LPL activity. Carriers of a specific LPL mutation that reduces LPL activity, had higher TG levels (+78%) and almost five-fold higher CHD risk. Other substitution mutations were associated with smaller changes in LPL activity and CHD risk.
Also loss-of-function mutations in co-factor ApoC-II as well as ApoA-V have been described to be associated with elevated TGs. The opposite is seen when APOC3 is mutated. For instance, a cohort of Amish subjects who are carrier of a mutation in APOC3, had 46% lower TG than non-carriers and 65% lower risk of coronary artery calcification. Recently, ANGPTL4 mutations have also been found to associate with lower TG levels and CAD risk.
Genome-wide association studiesGenome-wide association study (GWAS) search have identified common genetic variants that represent CHD susceptibility loci in gene regions encoding ApoC-III, ApoA-V, ANGPTL3 and ANGPTL4. Multivariate analysis on identified SNPs that affect TG levels showed a strong association of TGs with CHD, after adjusting for both LDL-c and HDL-c effect size.
An epigenome-wide association study revealed that methylation at 4 sites of carnitine palmitoyltransferase 1A was strongly associated with TG and VLDL-c levels.
Mendelian randomisation studies have pointed at a relationship between three common APOA5 variants and non-fasting TG levels and calculated remnant cholesterol levels and risk of myocardial infarction. Other Mendelian randomisation studies found that remnant cholesterol levels correlated strongly with non-fasting TG levels and with observed CHD risk. Genetic variants in LPL were causally related to lower TG levels.
Mendelian randomisation studies
A Mendelian randomisation meta-analysis showed that an unrestricted allele score based on 67 SNPs known to be associated with TG levels, was associated with CHD as well. The same was true for a restricted allele score of SNPs that were only associated with TGs (not with HDL-c and LDL-c).
Thus, genetic data confirm the epidemiologic and clinical data and point at a causative role for TGs and TLRs in ASCVD.
Clinical implicationsSince the effects of statins on TG levels are often insufficient, a TG-lowering agent may need to be added to this first line of treatment of lipid abnormalities. Prescription omega-3 fatty acids can be given as an adjunct to diet in adults with severe hypertriglyceridaemia (>500 mg/dL). Clinical trials demonstrated that prescription omega-3 fatty acids significantly reduced TGs in hypertriglyceridaemic subjects, with or without background statin therapy. Different types (containing eicosapentaenoic acid [EPA] and/or docosahexaenoic acid [DHA]) may have diverse effects on other atherogenic lipid parameters, including both beneficial and LDL-increasing effects.
These products are generally well-tolerated. TG-reducing niacin and fibrates, however, have tolerability issues and adverse side effects that may compromise treatment.
Omega-3 fatty acids may be beneficial in other ways than TG lowering, and effects on vascular and cardiac haemodynamics, arrhythmia, inflammation, endothelial function, thrombosis and production of anti-inflammatory mediators have been postulated.
Add-on therapy to statin therapy may therefore lower residual risk and provide CV benefit. The REDUCE-IT and STRENGTH outcomes trials are currently testing whether high dose prescription omega-3 fatty acid products reduce ASCVD in high-risk statin-treated patients.
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