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Genetics of cholesterol reveal insights into heart disease and diabetes drug targets

Genetics of cholesterol reveal insights into heart disease and diabetes drug targets

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A new study digging into the genetics of cholesterol also points to how doctors might one day use already-existing drugs to treat cardiovascular disease and diabetes.

In collaboration with the Million Veteran Program, Tim Assimes, MD, PhD, associate professor of medicine, analyzed genetic data from almost 300,000 veterans, scouring the information for clues to the genetic underpinnings of cholesterol. The scientists found 118 new genetic markers of cholesterol and confirmed 188 that were previously known.

In narrowing the focus, Assimes homed in on three mutations, all of which disrupted normal genetic function. That might sound like a bad thing, but it turned out that when the mutations were present in their respective genes, cholesterol levels were markedly improved.

And here’s the kicker, when the team of scientists ran deeper analyses on these mutations, comparing them against electronic health records and large databases of genetic information, they saw that the mutations either helped protect against heart disease, abdominal aortic aneurysm and diabetes (depending on which mutation was present).

A paper detailing the study published online in Nature Genetics today; Assimes is the corresponding author.

From our press release:

‘All of these mutations are loss-of-function variants, meaning they either substantially diminish or stop the function of the gene altogether,’ said [Derek Klarin, MD, clinical fellow in surgery at Harvard and one of the lead authors on the paper]. That makes a good case for developing a drug that copies what the mutation does; if a faulty PDE3B gene decreases risk for heart disease, it could be promising pharmaceutical inspiration. In this study, the PDE3B mutation was associated with lower triglycerides, higher HDLs and a 20 percent lower risk of heart disease.

As pharmaceutical fate would have it, there’s already a cheap generic drug on the market that’s used to treat patients with vascular disease, called cilostazol. As the release further describes:

The drug is typically only used to treat the symptoms of blockages in leg arteries to improve how far people with vascular disease can walk without pain. The next step is to investigate whether that same drug could wear multiple therapeutic hats.

Although the preliminary evidence is encouraging, Assimes cautions against prescribing cilostazol simply based on the association, and suggests waiting until a rigorous clinical trial has been performed to test out the drug’s functionality when it comes to treating heart disease.

Photo by Maira Gallardo

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