In a single gene, a path to fight heart attacks

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Two major studies by leading research groups published independently Wednesday identified mutations in a single gene that protect against heart attacks by keeping levels of triglycerides — a kind of fat in the blood — very low for a lifetime.

These findings are expected to lead to a push to develop drugs that mimic the effect of the mutations, potentially offering the first new class of drugs to combat heart disease in decades, experts say.

Statins, which reduce LDL cholesterol, another cause of heart disease, became blockbusters in the late 1980s. Since then, there have been no major new drugs approved for lowering heart disease risk. But experts caution that drug development takes years, and that there are no guarantees that new treatments will work as hoped.

Heart attacks are the leading killer in the United States, and about 720,000 Americans a year have them.

Although statins are effective in reducing heart attack risk, many users still often have high levels of triglycerides and go on to have heart attacks. So the results of the new studies are good news, said Daniel J. Rader,  director of the University of Pennsylvania‘‍s Preventive Cardiovascular Medicine and Lipid Clinic, who was not involved in the research. “We’ve been looking for something beyond statins,” Dr. Rader said. “After we have put people on high-dose statins, what else can we do? Essentially nothing.”

Experts differ in their estimates of how many Americans might be candidates for a triglyceride-lowering drug. If the eligible group included all adults with triglyceride levels of 200 or more — the normal level is 150 or less — that would mean about 20 percent of adult Americans. If it was just those with the highest levels, above 500, then 2 percent to 3 percent of adults would qualify.

The discovery announced Wednesday was hinted at in 2008 in a much smaller study in the Amish, conducted by researchers from the University of Maryland’s medical school. One in 20 Amish people has a mutation that destroys a gene, APOC3, involved in triglyceride metabolism, as compared with 1 in 150 Americans generally. The scientists were intrigued but did not have enough data to nail down the gene’s role in heart attacks.

Sam, a 55-year-old Amish farmer who declined to have his last name published, saying he was uncomfortable about being conspicuous, has such a beneficial mutation. He recalls little heart disease in his family. On a cold day last fall, as an icy rain fell outside, he sat at a small wooden table in his daughter’s house and laid out a sheet of paper which showed that he had a triglyceride level of 45. The average in the United States is 147. “It’s nice that something came out that is positive,” he said.

Triglycerides have long puzzled researchers, although they are routinely measured along with cholesterol in blood tests and are often high in people with heart disease. Many experts were unconvinced that they actually caused heart attacks. Clinical trials of drugs that lowered triglycerides by a small amount added to doubts about their role in heart attacks. The drugs had no effect on heart attack rates.

As for triglycerides themselves, “do they just keep bad company, or are they independently doing something to risk?” asked Robert Hegele, a heart disease expert at Western University in London, Ontario, who was not involved with the new studies.

Those studies, published in The New England Journal of Medicine and funded by the National Institutes of Health and the European Union, provide “a very, very strong type of evidence,” Dr. Hegele said, that triglycerides are, in fact, a cause of heart attacks.

The work began several years ago, when researchers at the Broad Institute of Harvard and MIT starting searching through an enormous data set drawn from 70 studies involving 200,000 people to see if there were tiny genetic changes near or in genes that seemed to lead to very high or very low amounts of triglycerides in the blood. They also asked whether people who happened to have a higher or lower triglyceride level also had a higher or lower incidence of heart attacks. The researchers discovered that people with a genetic predisposition to higher triglyceride levels had more heart attacks and those with genetically lower triglyceride levels had fewer.

Their study, published last year in Nature Genetics, did not isolate individual genes, though; it just pointed to signposts on the long stretch of 30 million DNA letters that were near the genes. So the investigators began a hunt for the genes themselves. To that end, they mapped the genes of 3,734 Americans, about 2,500 of whom were white and the balance African-American. The researchers reported the results of that effort Wednesday.

One gene, APOC3, stood out. The scientists found four mutations that destroyed the function of this gene. The Amish study had discovered that people with such a mutation could drink a big rich milkshake, loaded with fat, and their triglyceride levels did not budge. For everyone else, they spiked. The new studies show what that means to people’s health.

“Those who carry the gene mutations have a 40 percent reduction in triglyceride levels and a 40 percent lower risk of heart disease,” said Sekar Kathiresan of Massachusetts General Hospital and the Broad Institute, who was the gene project’‍s lead researcher. Now, Dr. Kathiresan added, “there is a route to heart attacks that is independent of LDL,” referring to the form of cholesterol associated with heart disease.

The other study, led by Anne Tybjaerg-Hansen of Copenhagen University Hospital, used data from 75,725 subjects to learn whether low triglyceride levels were linked to a reduced heart attack risk. They were. The researchers also asked whether people who had mutations destroying the APOC3 gene had fewer heart attacks. They did. Those with such mutations had a 44 percent reduction in triglycerides and a 36 percent lower heart attack risk. The Danish data, Dr. Kathiresan said, “are eerily consistent with our data.”

“It is incredible how reproducible the finding is,” he added. Yet the two groups worked independently, with The New England Journal of Medicine coordinating publication of their studies.

For the University of Maryland scientists who conducted the 2008 Amish study, the new finding shows that their hypothesis about the gene was correct. Those with the mutation had less calcification of their arteries, an indication that they had less heart disease. But the Maryland group was not able to say if those people also had fewer deaths from heart disease. Toni Pollin, lead researcher for the study, explained: “To really find out if it is related to heart disease, we’d need to follow people over time. And the Amish use hospitals a lot less than other people, so it is hard to document the cause of death.”

University of Maryland


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