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Rare mutations may highlight promising heart disease target
CAMBRIDGE, Mass.—Coronary artery disease is the most common form of heart disease, coming in as the number one cause of death in the United States and a leading cause of death worldwide. Three types of fat that circulate in the bloodstream— low-density lipoproteins (LDL cholesterol), high-density lipoproteins (HDL cholesterol) and triglycerides—are known to affect an individual’s risk of heart disease.
Traditionally, the bulk of research efforts into heart disease have been focused on LDL, the “bad” cholesterol; the casual link between LDL and heart disease is well established, and most statins target this type of cholesterol. The nature of the relationship between heart disease and HDL and triglycerides is not as elucidated, however. Observational studies have shown that HDL, or “good” cholesterols, levels and triglycerides can predict future heart disease, but it isn’t known what must change to have an effect on heart attack rates: HDL levels, triglycerides or both.
What is known, and was established in 2012 in a genetic study led by Sekar Kathiresan, a Broad associate member and director of preventive cardiology at Massachusetts General Hospital, and colleagues, is that while lowering LDL levels can mitigate a patient’s risk of heart disease, there is no such causal link between HDL and disease; increasing one’s levels of HDL does not lower their heart disease risk. Genomic investigation to determine the link between triglycerides and heart disease, however, did reveal a pattern of association between triglycerides and coronary artery disease, suggesting a causal link.
A team of researchers from the Broad Institute of MIT and Harvard, Massachusetts General Hospital and their colleges joined forces to more closely examine the role triglycerides play in heart disease.
“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,” said senior author Kathiresan. “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.”
After sequencing the exomes of close to 4,000 people, the researchers discovered four mutations, all of the APOC3 gene, linked to lower blood triglycerides. The APOC3 protein is primarily produced in the liver and then released into the bloodstream, where it is thought to prevent the removal of triglyceride-rich lipoproteins from the blood. Those with APOC3 mutations present with nearly half the normal levels of the protein in their blood, which is thought to allow triglyceride-rich lipoproteins to be cleared more rapidly so less enters the blood and the walls of coronary arteries. Individuals with just one of the mutations presented with triglyceride levels that were almost 40 percent lower than normal: standard levels are less than 150 milligrams per deciliter (mg/dL), and those with APOC3 mutations saw levels in the area of 85 mg/dL.
To elucidate the connection between the mutations and heart disease risk, the team analyzed more than 110,000 patients samples, genotyping the relevant parts of the APOC3 gene and comparing heart attack rates in those with one of the four mutations to those with normal copies of the gene. Carriers were found to have a risk of coronary heart disease 40 percent lower than that of people without any mutations.
“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.
“Although statins remain a powerful arrow in the quiver, the notion of residual risk of coronary heart disease continues to be a significant clinical problem,” Kathiresan added in a statement. “Our study really reinvigorates the idea of lowering triglycerides and specifically, by blocking APOC3, as a viable therapeutic strategy for addressing residual risk.”
Support for this research came from the National Heart, Lung and Blood Institute of the U.S. National Institutes of Health, among other sources. The results were published in the New England Journal of Medicine on June 18 in a paper titled “Loss-of-function mutations in APOC3, triglycerides and coronary disease.”