New drug targets heart disease gene
A study that sorted the good fats from the bad identified triglycerides as a potential culprit causing heart disease. That may provide new options for preventive treatment. Elizabeth Finkel reports.
Fats have been linked to heart disease since the 1950s, but we still don’t know exactly which ones are the worst offenders. There are many kinds of fats circulating in our bloodstreams – most infamously cholesterol – and the challenge over the past 50 years has been picking the villains from the bystanders.
Now two new studies show that people with a genetic quirk that affects fats known as triglycerides have a reduced risk of heart disease – by up to 40%. And researchers have already developed a promising new drug that targets the gene in question.
From our digestive systems, fats enter our bloodstreams and are taken up by our livers. Once there, they are repackaged and sent out for storage in fat cells. But this repackaging is where the problem lies. Fats such as cholesterol and triglycerides are bundled inside a scaffold of proteins, forming a variety of lipoproteins, and these protein-fat combinations determine how fats behave in our arteries.
For example, we know that high levels of one type of lipoprotein that binds cholesterol (LDL cholesterol) increase the risk of heart disease because they tend to dump cholesterol within the walls of arteries, the process called atherosclerosis. On the other hand, another variety, high density lipoprotein (HDL), appears to be protective, probably because it helps clear cholesterol from artery walls.
To better target drugs, we need to know if and why fats
are the cause of heart disease.
We also know that drugs such as statins that reduce levels of LDL cholesterol also reduce the risk of heart disease – by 37% according to one UK study. But what about other fats and their lipoprotein bundles?
If HDL helps clear cholesterol, increasing its levels should decrease the risk of heart disease. But a drug designed to do that, dalcetrapib, did not reduce heart disease, a 2012 study in New England Journal of Medicine (NEJM) showed. Bronwyn Kingwell, at Baker IDI Heart and Diabetes Institute in Melbourne believes the drug might not have produced fully-functional lipoproteins.
“There’s been a danger of commercial developments getting ahead of the science,” she says.
To better target drugs, we need to know if and why fats are the cause of heart disease. Numerous studies have shown a correlation between lower triglyceride levels and reduced heart disease risk. But is it a truly causal relationship? Rather than risk picking the wrong target, an international group of researchers – the Triglycerides and High-Density Lipoprotein Working Group of the Exome Sequencing Project – took advantage of natural genetic experiments to ask questions about triglycerides. They read the DNA of 3,700 people and also measured their triglyceride levels. While there was typical biological variation in the triglyceride levels, some people stood out with levels that were 40% lower than average. Remarkably each of them carried a mutation in exactly the same gene – APOC3.
The gene’s involvement was no great surprise. One of its known activities is to block the clearance of triglyceride-transporting lipoproteins from the bloodstream. But in these rare patients one copy of the gene was “broken”, allowing the lipoprotein and its triglycerides to be cleared from the bloodstream more quickly.
A 2008 study had also fingered the same gene in 5% of the Amish community. These people showed a similar reduction in triglyceride levels and hints that they are protected from fats building up in arteries.
To test whether the APOC3 mutations found in the current study lowered the risk of heart disease, the team tested a population of 110,000 people. About 500 of them had the mutation in APOC3. Not only were their triglyceride levels 40% lower, they also had a 40% lower risk of cardiovascular disease.
A Danish study published along with the US research in the 18 June issue of the NEJM, made the same findings after reading the sequence of the APOC3 gene in 10,333 people. “It’s eerily consistent,” says Sekar Kathiresan, one of the leaders of the US project based at Massachusetts General Hospital and the Broad Institute.
“It’s terribly important to determine whether an association between two factors is causal or not,” says Paul Nestel, also from the Baker Institute. “This genetic study is as close as you can get to showing a causal association [between triglycerides, APOC3 and heart disease].”
US company ISIS pharmaceuticals already has a drug in trial that works by lowering the output of the APOC3 gene. Fish oils can also reduce triglyceride levels, but only by 10%, says Kathiresan, and that may not be sufficient to have a cardiovascular effect. The same may apply to a drug called fenofibrate that also lowers triglyceride levels a little. But the new ISIS drug can lower triglyceride levels by 70%. The NEJM papers are certainly welcome news for the company. “We’re weighing how we want to take full advantage of this breakthrough,” ISIS CEO Stanley Crooke told the online medical news site Medscape. “We have a great deal of licensing interest for this drug.”