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Loss-of-function mutations in APOC3 gene linked to lower CV risk
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Loss-of-function mutations in the APOC3 gene are associated with lower levels of triglycerides and reduced risk for CHD and ischemic CVD, according to two studies published in The New England Journal of Medicine.
In one study, the triglycerides and HDL working group of the NHLBI’s Exome Sequencing Project found four mutations of APOC3, three of them loss-of-function mutations, associated with lower levels of plasma triglycerides and reduced risk for CHD. In the other, a Danish research team found that APOC3 loss-of-function mutations were associated with lower levels of triglycerides and reduced risk for ischemic vascular disease and ischemic heart disease.
CHD risk
In the Exome Sequencing Project, researchers sequenced 18,666 genes in 3,734 people of European or African descent. They performed tests to determine whether rare mutations were associated with plasma triglyceride levels. For the mutations determined to be associated with triglyceride levels, the researchers evaluated their association with CHD in 110,970 people.
The researchers found four mutations of APOC3 linked to lower plasma triglyceride levels. Three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T), and the fourth was a missense mutation (A43T).
They found that approximately 1 in 150 participants were heterozygous carriers of at least one of the four mutations.
Those who had at least one of the mutations had triglyceride levels 39% lower (P<1x10-20) and circulating levels of APOC3 46% lower (P=8x10-10) compared with those who did not, the researchers found.
The 498 carriers of at least one mutation had a CHD risk 40% lower compared with the 110,472 noncarriers (OR=0.6; 95% CI, 0.47-0.75), according to the researchers.
“The results of our study highlight the potential usefulness of naturally occurring loss-of-function mutations in guiding the selection of therapeutic targets,” the researchers wrote.
Ischemic CVD risk
In the Danish study, Anders Berg Jørgensen, MD, PhD, and colleagues analyzed 75,725 participants from two general-population studies. They tested whether low levels of nonfasting triglycerides were associated with reduced risk for ischemic vascular disease and ischemic heart disease. Median follow-up was 4 years.
They found that loss-of-function mutations in APOC3, specifically R19X, IVS2+1G→A and A43T, were associated with reduced levels of nonfasting triglycerides, and tested whether they were also associated with reduced risk for ischemic vascular disease and ischemic heart disease.
Median follow-up was 34 years, during which 10,797 participants developed ischemic vascular disease and 7,557 of those who developed ischemic vascular disease also developed ischemic heart disease.
Jørgensen, of University of Copenhagen, and colleagues found that those with nonfasting triglyceride levels <1 mmol/L had a lower incidence of CVD compared with those with nonfasting triglyceride levels >4 mmol/L (ischemic vascular disease, HR=0.43; 95% CI, 0.35-0.54; ischemic heart disease, HR=0.4; 95% CI, 0.31-0.52).
Compared with those who had no loss-of-function mutations in APOC3, those with at least one had 44% lower nonfasting triglyceride levels (P<.001), according to the researchers.
Compared with those who had no loss-of-function mutations in APOC3, those with at least one had lower incidence of and risk for ischemic vascular disease (HR=0.59; 95% CI, 0.41-0.86) and ischemic heart disease (HR=0.64; 95% CI, 0.41-0.99), Jørgensen and colleagues found.
A fourth mutation, V50M, was not associated with triglycerides or other lipid measures, but had a nonsignificant correlation with ischemic vascular disease, so it having an effect on ischemic vascular disease cannot be ruled out, the researchers wrote.
For more information:
Jørgensen AB. N Engl J Med. 2014;doi:10.1056/NEJMoa1308027.
Disclosure: See the full studies for the researchers’ relevant financial disclosures.