Physicians' Academy for Cardiovascular Education

APOC3 mutations associated with low triglycerides and reduced CV risk

Jørgensen AB et al., NEJM 2014 - N Engl J Med. 2014 Jun 18

 
In observational studies, high plasma levels of nonfasting triglycerides (TG) have been associated with an increased risk of coronary heart disease and ischaemic cardiovascular (CV) disease. Also genetic studies have suggested that plasma TG-rich lipoproteins directly influence the risk of coronary heart disease [1] and ischaemic CV disease [2,3].
To date, it is however unknown whether mutations in coding sequences of proteins that affect plasma TG levels are associated with a reduced risk of coronary heart disease and ischaemic CV disease in the general population.
Apolipoprotein C3 is a component of remnant particles that is associated with high levels of TG. Apolipoprotein C3 increases plasma TG levels. A loss-of-function mutation in the APOC3 gene has been associated with reduced TG levels and with lower coronary artery calcification, a surrogate marker for atherosclerosis [4]. Two separate study groups now investigated the consequences for carriers of loss-of-function gene variants of the APOC3 gene in the general population.
 

Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease

The TG and HDL Working Group of the Exome Sequencing Project
N Engl J Med. 2014 Jun 18. [Epub ahead of print]
 
This study sequenced the exomes of 3734 people to identify rare loss-of-function variants of APOC3. People carrying these variants had significantly lower TG levels. Four rare APOC3 mutations were identified. Carriers of any rare APOC3 mutation had 39% lower plasma TG levels. HDL-c levels were 22% higher and LDL-c levels were 16% lower in carriers.
Subsequently, the association of APOC3 gene variants with the risk of coronary heart disease was evaluated in data of 14 studies of over 110.000 participants (34.002 patients with coronary heart disease and 76.968 controls). This analysis revealed that people with any of these loss-of-function mutations (n=498 heterozygous for at least one loss-of-function mutation) had a 40% lower risk for coronary heart disease than noncarriers of these gene variants (OR: 0.60, 95%CI: 0.47-0.75, P=4x10-6).  Circulating levels of APOC3 in persons with one mutant allele were 46% lower (P=8x10-10)  than in  noncarriers.
Conclusion:  About 1 in 150 persons in these analyses carried any one of four mutations in the protein-encoding region of the APOC3 gene. The authors conclude that ‘loss of the APOC3 function confers protection against clinical coronary heart disease’. A potential primary mechanism linking APOC3 to heart disease remains to be elucidated.
 

Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease

Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A

N Engl J Med. 2014 Jun 18. [Epub ahead of print]
 
The second study analysed data from over 75.000 participants in two Danish prospective studies. Risks of ischaemic vascular disease and ischaemic heart disease decreased in a stepwise fashion as a function of decreasing nonfasting TG levels.
13 genetic variants were identified in the coding regions and exon-intron boundaries of the APOC3 gene. Three rare variants were associated with substantially reduced nonfasting TG levels. Allele frequency of these three variants in the two cohorts combined was 1 in 580 alleles, or 1 in 290 participants.
People with these APOC3 loss-of-function gene variants had 44% lower TG levels (-0.77 mmol/L) than noncarriers. Apolipoprotein B levels were 16% lower (17 mg/dL) and HDL-c levels and apolipoprotein A1 were increased with 24% (0.38 mmol/L) and 9% (15 mg/dL) respectively. Carriers had a 41% lower risk of ischaemic vascular disease (HR: 0.59, 95%CI: 0.41-0.86, P=0.007) and 36% lower risk of ischaemic heart disease (HR: 0.64, 95%CI: 0.41-0.99, P=0.04).
Conclusion:  Life-long low levels of non-fasting TGs due to one of three loss-of-function mutations in APOC3 are associated with lower risk of ischaemic vascular disease and ischaemic heart disease in the general population.
 
The authors of both publications speculate about APOC3 being an attractive therapeutic target, although the precise mechanism of how loss of APOC3 function might be atheroprotective remains to be determined.  Since a range of associated biomarkers were also altered in APOC3 carriers, the separate effects on CV disease could not be disentangled.
 
Find both articles on Pubmed:
Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease.
Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease.
 

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. Jørgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG, Ty­bjærg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 2013;34:1826-33.
3. Varbo A, Benn M, Tybjærg-Hansen AL, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.
4. Pollin TI, Damcott CM, Shen H, et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 2008;322:1702-5.