New research on DNA reveals four rare gene mutations that can lower the level of triglycerides and decrease the risk of coronary heart disease by 40 percent.

The mutations affect a gene called APOC3, according to research published this week in the New England Journal of Medicine, and play into the role of triglycerides, which is a type of fat in human blood. High triglyceride levels are a major factor in heart disease.

The most common form of heart disease is coronary artery disease and it is the leading cause of death in the United States and a major cause of death worldwide, according to a release on the study.

Fats in the blood have long been associated with risk of the disease. These fats, or lipids,  include low-density lipoproteins (LDL cholesterol), high-density lipoproteins (HDL cholesterol), and triglycerides.

"The combination of our genetic results, together with recent clinical trials of drugs that raised HDL levels but failed to prevent heart disease, are turning decades of conventional wisdom on its head," explains senior author Sekar Kathiresan, an associate member in the Broad Institute's Program in Medical and Population Genetics and director of preventive cardiology at Massachusetts General Hospital.

"HDL and triglycerides are both correlated with heart attack, and have an inverse relationship with one another -- the lower the HDL, the higher the triglycerides. It has long been presumed that low HDL is the causal factor in heart disease, and triglycerides are along for the ride. But our genetic data indicate that the true causal factor may not be HDL after all, but triglycerides," Kathiresan added.

The APOC3 protein is mainly created in the liver and then works into the blood stream. The mutations uncovered in the NEJM study all decrease APOC3 activity -- carriers have roughly half the normal level of APOC3 protein present in their blood.

Researchers believe this then lifts "the damper on triglyceride-rich lipoproteins," allowing them to be cleared more quickly so less enters the blood and relatedly, the walls of the coronary arteries, where the ultimate damage is done.

A previous large genetic study two years ago, run by Kathiresan and his team, did not find a causal association between the so-called "good cholesterol," HDL, and heart disease, challenging the long-held view that increasing HDL levels will lower the risk of heart disease.  

"These genetic studies are consistent with the recent negative results from multiple clinical trials of agents that raised HDL substantially, but failed to lower risk of heart disease," notes the release.

Regarding the most recent study, the scientists believe it indicates that decreasing triglycerides could have a substantial impact on avoiding heart disease. This, in turn, may lead to better heart disease prevention and treatment.

"Based on our findings, we predict that lowering triglycerides specifically through inhibition of APOC3 would have a beneficial effect by lowering disease risk," said senior co-author Alex Reiner, a member of the Public Health Sciences Division at Fred Hutchinson Cancer Research Center and a research professor of epidemiology at the University of Washington's School of Public Health.

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