DEFINING TOMORROW'S VASCULAR STRATEGIES
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13 June 2014
APOC3: a potential target for residual cardiovascular risk?
Two recent genetic studies lend further support for elevated triglycerides as a causal factor for coronary heart disease. The studies showed that individuals with loss-of-function mutations in the APOC3 gene had low levels of triglycerides and reduced risk of cardiovascular disease. These data strengthen the case for elevated triglycerides, a marker for triglyceride-rich lipoproteins and their remnants, as an important cause of residual cardiovascular risk.
The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute; Crosby J, Peloso GM, Auer PL et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;371:32-41.
STUDY SUMMARY: TG and HDL Working Group
Objective To address two unanswered questions:
i) to what extent do rare DNA sequence variants contribute to individual variation in plasma triglyceride levels and the risk of coronary heart disease (CHD) at the population level, and
ii) are there specific genetic variants that might lower triglyceride levels and reduce the risk of CHD? 
Study design The study was part of the Exome Sequencing Project of the National Heart, Lung, and Blood Institute (NHLBI) (https://esp.gs.washington.edu/drupal). This included seven population-based cohorts, and subjects in a study of early-onset myocardial infarction (MI).
Study population 3,734 subjects (2,082 of European and 1,652 of African descent) were included in the Discovery analysis. Sequencing data were independently replicated in 34,432 and 7,239 subjects of European and African descent, respectively.
 
Regression models were based on data from 110,970 subjects (34,002 with CHD) from 14 studies, and 3,237 subjects from the Framingham Heart Study.
Primary variable • Carriage of loss of function mutations (R19X, IVS2+1G→A, IVS3+1G→T) or a missense mutation (A43T) in APOC3.
• Plasma triglyceride levels
• Odds ratio for the association of loss-of-function carrier status (heterozygous for any of four mutations described above) with the risk of CHD.
Methods Discovery analysis: Linear regression to test the association of plasma triglyceride levels with identified DNA sequence variants. The single variant association analysis was limited to variants with a frequency >0.1%. APOC3 was most strongly associated with plasma triglyceride levels.
Testing for association of APOC3 mutations with CHD was performed using proportional hazards regression models.
Main results Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four APOC3 mutations. Triglycerideride levels were 39% lower in carriers compared with noncarriers (P<1×10−20).
CHD risk was 40% lower in carriers (n=498) of any of these rare APOC3 mutations compared with noncarriers (n=110,472); odds ratio 0.60(95% confidence interval [CI] 0.47 to 0.75), p = 4×10−6).
Author's conclusion Rare mutations that disrupt APOC3 function are associated with lower levels of plasma triglycerides and apoC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease.
STUDY SUMMARY: Jørgensen et al.
Objective To test whether lifelong low levels of nonfasting triglycerides due to mutations in the APOC3 gene are associated with a reduced risk of ischaemic cardiovascular disease in the general population.
Study design Genetic analysis
Study population 75,725 subjects in two general population studies (Copenhagen City Heart Study and the Copenhagen General Population Study). All subjects were white and of Danish descent.
Primary variable • Carriage of loss of function mutations (R19X, IVS2+1G→A, A43T) in APOC3.
• Plasma triglyceride levels
• Odds ratio for the association of loss-of-function carrier status with the risk of ischaemic vascular disease or ischaemic heart disease
Methods Researchers first tested whether low levels of nonfasting triglycerides were associated with reduced risks of ischaemic vascular disease and ischaemic heart disease. The reseachers then tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischaemic vascular disease.
Main results During follow-up 10,797 subjects developed ischaemic vascular diseaseand 7,557 of these subjects developed ischaemic heart disease.
Compared with noncarriers, subjects who were heterozygous carriers of a loss-of-function mutation in APOC3 had 44% lower non-fasting triglyceride levels (p<0.001).  These individuals also had significantly lower risk for ischaemic vascular disease (risk reduction 41%, hazard ratio 0.59 [95% CI 0.41 to 0.86]; p = 0.007) and ischaemic heart disease (risk reduction 36%, hazard ratio 0.64 [95% CI 0.41 to 0.99], p = 0.04).
Author's conclusion Loss-of-function mutations in APOC3 are associated with low levels of triglycerides and a reduced risk of ischaemic cardiovascular disease.
COMMENT

Recent research has fuelled renewed enthusiasm for a role for elevated plasma triglycerides, a marker for triglyceride-rich lipoproteins and their remnants, in residual cardiovascular risk. As discussed on this website, there is now convincing supportive evidence from genetic studies to show that elevated triglycerides are causal for coronary heart disease.1,2 This in turn raises two key questions: first, are there specific variants that are associated with low plasma triglycerides; and two, does carriage of such variants confer reduced risk for cardiovascular disease?

The results of these two genetic analyses provide answers to both questions. Both consistently show that carriage of mutations (either loss of function or missense mutations) in the gene encoding triglyceride-rich lipoprotein-associated apolipoprotein c3 (alternatively referred to as apoCIII) (APOC3) confers ~40% reduction in cardiovascular risk in the setting of lifelong exposure to low triglycerides. Mechanistic studies also lend support.  Extracellularly, apc3 inhibits hydrolysis of triglyceride-rich lipoproteins by lipoprotein lipase, and also reduces uptake of triglyceride-rich remnant lipoproteins by the liver.3,4 Additionally, within the cell, apoc3 promotes triglyceride synthesis and very-low density lipoprotein (VLDL) assembly and secretion.5 All of these mechanisms would result in high levels of triglyceride-rich remnant lipoproteins in the plasma, linked with atherosclerosis progression and risk for cardiovascular disease.6

The key question then is whether targeting apoc3 offers the possibility of testing whether such an innovative pharmacological reduction in plasma triglycerides confers reduced risk of cardiovascular disease events, which has so far proved elusive. Novel investigational approaches, such as the development of an antisense oligonucleotide to apoC3 which has been shown to lower plasma triglycerides,7 may offer the opportunity to test this in the near future.

References 1. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013;45:1345-52.
2. Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat Genet 2013;45:1274-83.
3. Ginsberg HN, Le NA, Goldberg IJ et al. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI: evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest 1986;78:1287-95.
4. Clavey V, Lestavel-Delattre S, Copin C, Bard JM, Fruchart JC. Modulation of lipoprotein B binding to the LDL receptor by exogenous lipids and apolipoproteins CI, CII, CIII, and E. Arterioscler Thromb Vasc Biol 1995;15:963-71.
5. Qin W, Sundaram M, Wang Y et al. Missense mutation in APOC3 within the C-terminal lipid binding domain of human ApoC-III results in impaired assembly and secretion of triacylglycerol-rich very low density lipoproteins: evidence that ApoC-III plays a major role in the formation of lipid precursors within the microsomal lumen. J Biol Chem 2011;286:27769-80.
6. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
7. Graham MJ, Lee RG, Bell TA III et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013;112:1479-90.
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