High 'good' cholesterol not always a good sign

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The University of Pennsylvania’s Daniel J. Rader said a genetic mutation may interfere with “good” cholesterol’s ability to rid the body of the bad stuff.

Evidence has been mounting for a few years that raising "good" cholesterol levels is not necessarily helpful in preventing heart disease.

A new study led by University of Pennsylvania researchers explains a piece of that complicated puzzle, at least for people with a particular genetic quirk.

Good cholesterol is called that because it is a measurement of how much of the waxy, artery-clogging stuff is being shuttled to the liver for disposal, carried by high-density lipoprotein (HDL) complexes that Penn's Daniel J. Rader likens to "trash trucks."

But in some patients, a genetic mutation impairs the liver's ability to empty the trash trucks, leaving them with higher-than-normal HDL levels, Rader and colleagues reported Thursday afternoon in the journal Science.

"Imagine the guys who unload the trucks at the dump go on strike," he said. The trucks "are driving around fully engorged with trash. And no trash collection is happening because they don't have any room to pick up more trash."

It remains true that on average, higher HDL cholesterol levels are associated with a lower risk of heart disease. But that doesn't mean higher HDL is always protective, because it is difficult to say whether an individual's high HDL means efficient trash pickup or inefficient disposal, said Rader, chair of the department of genetics at Penn's Perelman School of Medicine.

Several drugs that raise good-cholesterol levels have been found to confer little or no protection against heart disease. Yet HDL levels also go up in people who exercise and keep their weight under control, suggesting that for them, the number serves almost as a marker of heart-healthy behavior, Rader said.

The new study results are "intriguing," but are a long way from changing the advice you get at the doctor's office, said Steven E. Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic, who was not involved with the research.

"The clinical implications remain to be determined," Nissen said.

Rader acknowledged as much, though he said he hopes the research will lead to new drugs. Meanwhile, statins, which lower LDL - "bad" cholesterol - remain an important weapon against heart disease in at-risk patients.

The impaired cholesterol disposal mechanism described in the new study is caused by a mutation found in six out of 100,000 people. Data from the Ashkenazi Genome Consortium at Columbia University show that in people descended from eastern and central European Jews, the mutation is much more common - present in perhaps one in 20 people.

Rader predicted that scientists would identify still other mutations that nudge the body's ability to handle cholesterol one way or the other.

The mutation reported in the study was initially identified in a 67-year-old woman of Ashkenazi descent. She had the mutation in both copies of a gene that was already known to play a role in cholesterol disposal in mice, and her HDL number was sky-high: 152.

For men, an HDL number in the mid-40s is considered normal; for women, normal is in the mid-50s.

The researchers then found that mutation in 15 additional patients, each of whom had it in just one copy of the gene in question. Their HDL levels were not as high as the first woman, but were still higher than normal.

In order to determine what the mutation did in humans, the scientists needed a way to study the patients' liver cells without the risk associated with a liver biopsy.

So they took blood cells from each patient and turned them into liver-like cells. They did so by first coaxing the blood cells to turn into stem cells, using a process developed by scientists who won the 2012 Nobel Prize in medicine.

In laboratory experiments, the liver-like cells with the mutation in question did have a reduced ability to dispose of cholesterol.

Then the researchers reviewed genetic information for nearly 140,000 patients, finding that patients with the mutation were about 80 percent more likely to have heart disease than those who did not.

The HDL number in these patients with the mutation was 10 to 15 points higher than normal for their age and sex, Rader said.

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