The APOC3 protein is mainly made in the liver and pours out into the blood stream. There, it is thought to prevent the removal of triglyceride-rich lipoproteins from the blood in a few distinct ways, particularly by delaying their clearance following a meal. 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. This is thought to lift the damper on triglyceride-rich lipoproteins, allowing them to be cleared more quickly so less enters the blood and the walls of the coronary arteries, where the ultimate damage is done.
One of the
APOC3 mutations identified by Kathiresan and his colleagues had been previously found in a 2008 study of heart disease in the Lancaster Amish. That work also uncovered an association with lower blood triglyceride levels. There were hints that the mutation might protect against heart disease - carriers had less calcium in their coronary arteries, a sign of accumulating fat - but more work was needed to understand the connection to clinical disease events such as heart attack.
To definitively establish the relationship between these mutations and the risk of coronary heart disease - specifically, the incidence of heart attack - the researchers analyzed over 110,000 patient samples. They read out, or "genotyped" the relevant parts of the
APOC3 gene, and compared heart attack rates in those carrying mutations to those without them.
In the carriers, they found a 40% lower risk of coronary heart disease, suggesting inhibition of APOC3 as a new potential strategy for therapeutic development.
"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 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.
Triglyceride-lowering therapies exist, but those that are currently available have not been proven yet to stave off heart disease. This lack of effect in the studies conducted so far could be due to the therapies' relatively modest impact on triglyceride levels compared to the sizeable effect of
APOC3 mutations, which lower triglyceride levels by 80 to 90 mg/dL. The current therapies likely also act through multiple molecular targets.
Triglyceride-lowering drugs reflect an important clinical need. Doctors have recognized that even after patients are treated with drugs to lower LDL cholesterol, some still succumb to heart attacks. This so-called "residual risk" suggests there are other biological mechanisms at play that can raise a person's risk of heart disease.
"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," said Kathiresan. "Our study really reinvigorates the idea of lowering triglycerides and specifically, by blocking APOC3, as a viable therapeutic strategy for addressing residual risk."
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