Flawed gene may cut heart disease risk
A massive study of more than 113,000 people published Wednesday by Boston researchers found that people with a flawed gene have modestly lower levels of “bad” LDL cholesterol and half the risk of heart disease than those with the normal, functioning gene.
The scientists do not know why the small decrease in cholesterol would have such a strong effect, but the finding suggests that a slightly lower level of bad cholesterol over a lifetime could be beneficial.
“My best guess is the reason we see a much larger difference in disease risk ... is the genetics is a reflection of lifelong differences,” said Dr. Sekar Kathiresan, director of preventive cardiology at Massachusetts General Hospital, who led the work. “The cumulative effect of slightly lower LDL over many years probably leads to a greater reduction in risk.”
The results, published in the New England Journal of Medicine, come a week before the highly anticipated announcement of the results of a nine-year study of a Merck & Co. drug that works in the same way as the rare gene mutations. The drug, called ezetimibe, works by disrupting a protein called NPC1L1, which is involved in the absorption of cholesterol in the gut. The rare gene mutations detected in the study also inactivate the protein.
Only the clinical trial of 18,000 patients by Merck can settle the question of whether the drug works, but the genetic finding lends support to attacking heart disease with that approach.
The research from Mass. General and the Broad Institute, a genome research center in Cambridge, is also the latest example of a powerful new approach that uses genome sequencing of very large populations of people to sift out rare mutations that protect against disease. Those results provide important clues that can help researchers understand which markers of heart health are truly causative.
Earlier this summer, the same team found evidence that people who have rare mutations that cause very low levels of a fat called triglycerides are 40 percent less likely to have heart disease than people without the mutations. The results suggested that triglycerides are a useful measure of heart health. Two years ago, the team found that people with rare gene mutations that caused high levels of “good” HDL cholesterol in the blood did not have a commensurate reduction in the risk of heart attack -- suggesting that higher HDL itself may not be protective.
“The more we can do this kind of work, that may keep us from false starts and blind alleys in developing new drugs,” said Dr. Harlan Krumholz, a cardiologist at Yale University School of Medicine who was not involved in the study. He added that just because a study shows a gene is important, that does not guarantee that a drug that takes the same approach will work. Instead, he said, the genetic studies help narrow down the number of strategies to use when developing therapies.
“This is more like you’re on a beach with a metal detector and lots of time the metal detector goes off and you don’t find any treasure, but you’re better off with a metal detector than digging anywhere on the beach,” Krumholz said. “What this may say is this might be a fruitful area for developing therapeutics.”
The new findings won’t be immediately useful to patients; the mutations that disable the gene are exceedingly rare, found in 1 of every 650 people. However, several physicians said that the study corroborates an idea that has been supported by other work: that lowering LDL cholesterol modestly over an entire lifetime may have beneficial effects that can’t be achieved by lowering cholesterol later in life, as is done in most drug trials.
The difference in LDL cholesterol measured between people with the mutations and those without was about 12 milligrams per deciliter -- about the same reduction that is seen when ezetimibe is given as a drug. In other cholesterol-lowering drug studies, it takes about three times as big a drop in LDL cholesterol as was seen in the new study, to get just a 20 percent reduction in heart disease risk, according to Dr. Neil Stone, a cardiologist at Feinberg School of Medicine at Northwestern University. The genetic study suggests that reducing cholesterol levels early, through lifestyle changes, could have powerful effects.
There could be other explanations for the reduction in the risk of disease. For example, the flawed gene impedes absorption of other molecules that could also play a role in heart health.
Several experts said the work suggests that people should be thinking about ways to reduce their LDL cholesterol level before doctors tell them they are at risk of a heart attack.
“This is an exciting study,” Stone said. “It allows us to see what small changes can do over a long time, and the idea that prevention is something that should last over your lifetime, that’s a terrific idea.”