APOC3 Mutations Tied to Low Triglycerides, Healthy Heart

Marlene Busko

June 23, 2014

BOSTON, MA and COPENHAGEN, DENMARK (updated) — People with a rare genetic mutation in the gene encoding apolipoprotein C3 (APOC3) not only have lower plasma triglyceride levels, they also have a decreased risk of developing coronary heart disease (CHD), researchers report in two independent studies published online June 18, 2014, in the New England Journal of Medicine[1,2]. This could eventually lead to the development of new drugs that mimic this genetic effect, although that potential therapy is far away.

"About one in 150 people in the US carry any one of four mutations in this [APOC3] gene and as a result have markedly lower levels of plasma triglycerides—about 40% lower," Dr Sekar Kathiresan (Massachusetts General Hospital, Boston), lead researcher of a US study, told heartwire . Importantly, people with these mutations also have a 40% lower risk for heart disease compared with noncarriers. A second study by Dr Tybjærg-Hansen (University of Copenhagen, Denmark) and colleagues reports "eerily similar findings" in a Danish population, he noted.

Although there is no specific drug available to target high plasma triglycerides and reduce clinical outcomes, lifestyle changes can "dramatically" lower triglyceride levels and prevent adverse cardiovascular events. Physicians should advise patients to get to a lean body weight, be physically active 150 minutes a week, cut back on excess carbohydrates, cut back on excess alcohol, and, if they have diabetes, make sure blood glucose is well controlled, he said.

Isis Pharmaceuticals, a small California company, is developing an orphan drug to lower plasma APOC3 for patients who have triglycerides levels that "are through the roof—over 1000 [mg/dL]," and in small clinical trials the drug lowered plasma triglyceride levels by 70%, according to Kathiresan. "I think other companies will be racing to catch up," he speculated.

Currently, fibrates and niacin are used to lower triglyceride levels and the US Food and Drug Administration (FDA) has also approved prescription fish oils (Lovaza, GlaxoSmithKline; Vascepa, Amarin Pharmaceuticals; and Epanova, AstraZeneca) for use in adults with triglyceride levels >500 mg/dL. None of these agents are approved by the FDA to reduce clinical outcomes.

Research Attention Shifting to Triglycerides

"We've known for over 40 years that LDL cholesterol is the key driver for atherosclerosis . . . and medications like statins that lower LDL cholesterol reduce the risk of heart attack," but the role for HDL cholesterol and triglycerides has been less certain, Kathiresan observed. Over the past 20 to 30 years, researchers have looked at ways to try to raise HDL-cholesterol levels to lower CVD risk, without success.

Recent studies have shown that, contrary to what might be expected, people with genetic mutations resulting in lifelong high plasma levels of HDL cholesterol do not have a lower risk of heart disease. "These [genetic] data and data from four different randomized trials . . . has really dampened the enthusiasm for [developing] HDL-cholesterol–raising therapies and [looking at] HDL cholesterol as a causal factor for heart disease," Kathiresan noted.

Thus research attention has shifted to triglycerides. The current study, conducted as part of the Exome Sequencing Project of the National Heart, Lung, and Blood Institute (NHLBI), aimed to investigate how rare variants in protein-coding sequences affect plasma triglyceride levels and risk of CHD.

The researchers sequenced the protein-coding regions of 18 666 genes in 3734 individuals with European or African ancestry who participated in the Exome Sequencing Project. They identified four rare mutations in APOC3 that were associated with reduced plasma triglyceride levels.

Next, they evaluated the association of these APOC3 mutations with the risk of CHD in 34 002 patients with CHD and 76 968 controls from 14 studies.

Circulating APOC3 levels were 46% lower and triglyceride levels were 39% lower in those with a rare APOC3 mutation compared with levels in noncarriers. The risk of CHD was 40% lower among the 498 carriers of a rare mutation compared with noncarriers.

Danish Findings Echo US Ones, "Desperate Search"

In the second study, Tybjærg-Hansen and colleagues analyzed data from 75 725 participants in two population-based studies in Denmark. The risks of vascular and heart disease decreased in a stepwise fashion as triglyceride levels decreased.

The researchers sequenced the coding regions of APOC3 in 10 333 participants. On average, patients with mutations in APOC3 had triglyceride levels that were 44% lower than other patients. Mutation carriers had a 41% lower risk of ischemic vascular disease and a 36% lower risk of ischemic heart disease, compared with noncarriers.

"Statins are the best-studied medicines for heart attack, and they work remarkably well, but most people who take statins still go on to have a heart attack," Kathiresan said. "Everybody's been desperately searching for [other therapies] beyond, of course, lifestyle changes, and unfortunately right now there aren't any."

However, there is now early "proof of principle" that it might be possible to develop a new class of pharmaceutical agents to protect against heart disease, he said.

Kathiresan reports grant support from Merck and the National Institutes of Health/NHLBI during the conduct of the study, grant support from Celera, and personal fees from Catabasis and American Genomics outside this work. Jørgensen has no conflicts of interest. Disclosures for the coauthors are listed at nejm.org.

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