Study Fails to Confirm Gene Variants as Heart Risk Factors

New method of measuring association holds promise, researchers say

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HealthDay Reporter

TUESDAY, April 10, 2007 (HealthDay News) -- Almost all of the 85 genetic variants previously identified as risk factors for heart disease have flunked a new, more definitive test, researchers report.

"We were unable to confirm as risk factors for acute coronary syndromes 85 genetic variants, because none were unequivocally validated in this large case-control study of 1,461 participants," said a report in the April 11 issue of the Journal of the American Medical Association.

"In their enthusiasm to publish work, people have identified genes where they found an association and put them forward without validating the finding in other populations," explained study author Dr. John A. Spertus, a professor of medicine at the University of Missouri at Kansas City. "We found that when we tried to replicate the findings in a completely different population, we couldn't."

Now, the work of finding genes related to heart disease must start over, because "at the end of the day, we don't have much of an idea which genes are involved in the development of risk for atherosclerotic heart disease," said Dr. Thomas Quertermous, chief of the division of cardiovascular medicine at Stanford University. "At the bottom line, we don't know anything."

That lack of knowledge is surprising and damaging, because "we would estimate that 40 percent of the risk for developing heart disease is genetic," Quertermous added. "We have not yet elucidated which genes are at the heart of that."

Until now, the search has involved looking for specific gene variants in limited numbers of people with heart disease, he explained. "It's like looking for a lost key under the lamppost, because that's where the lights are," Quertermous said. "We've been looking for favored genes, while the keys are probably out there in the dark."

This latest study involved a genetic analysis of 811 people with acute coronary syndrome and 650 individuals with no heart disease. The testing was done at the University of Missouri, while the lab work was done at Yale University. It found a statistically significant association with risk for only one of the gene variants and minor associations with four others.

With the new method, "we are going to look at 500,000 different variations on the human genome to see which areas are most different between cases and controls," Spertus said. "Then, we will try to find new genes in those areas. Then, someone else will try to verify the findings to be comfortable that they are real."

Some 10 to 12 whole-genome studies are getting under way in the United States, said Quertermous, who is involved in one of them. "For the first time, we will be able to find genes even if we don't know anything about them," he said. "Until now, we have just been taking guesses. We go through the entire genome, ranking positive-looking genes. Then, we will have replication studies, then more multiple rounds of replication."

The whole-genome approach is possible, because "the technology is available, and the costs are coming down dramatically," Spertus said.

In three to five years, Quertermous said, "we will have good data concerning which genes are associated with heart disease." The whole-genome technique has been applied with success to diabetes, he added.

Drug companies are watching the effort with enthusiasm, Quertermous said. "The only drugs on the market now treat risk factors for heart disease, such as high cholesterol," he said. "Once we know which genes and biological pathways are involved, then they can develop much better drugs that target the disease itself."

In a Finnish report in the same issue of the journal, injections of corticosteroids after heart surgery helped reduce the risk of atrial fibrillation by 37 percent. The abnormal heart rhythm increases the chances of stroke and other problems.

More information

The role of family history as a risk factor for heart disease is described by the American Heart Association.

SOURCES: John A. Spertus, M.D., professor, medicine, University of Missouri at Kansas City; Thomas Quertermous, M.D., chief, cardiovascular medicine, Stanford University, Stanford, Calif.; April 11, 2007, Journal of the American Medical Association

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