In a finding that could open the door to a broad new understanding of heart disease, researchers have identified what they say is the first genetic mutation directly linked to heart attacks.

The mutation was discovered in a study of 21 members of a large family with a history of heart disease. Thirteen of the family members had suffered heart attacks or developed serious coronary artery disease by the time they reached their early 60s, and researchers found that every one of them had the genetic defect. The eight others, all of whom were at least 45 years old, didn't have the mutation and had no obvious signs of severe disease.

"These people were hard-wired for a heart attack," says Eric J. Topol, chairman of cardiology at the Cleveland Clinic and co-lead investigator of the study. "It's not like you have a two-fold higher risk. It's 100%. If you have this gene, you are programmed for heart disease."

The report on the finding, being published Friday in the journal Science, is a major early milestone in an ambitious world-wide drive to unravel the genetic basis of coronary artery disease. Researchers at more than 20 academic centers are in hot pursuit of what are likely to be dozens of genes that bear on a person's heart-attack risk.

Scientists say the newly discovered defect, in a gene called MEF2A, is an unusually powerful mutation and is probably rare in the general population. Dr. Topol and his colleagues combed a genetic database of more than 800 heart patients and found that none of them had the defect. They also didn't find it among members of another large family that is plagued by heart attacks -- and, presumably, a different genetic abnormality. That suggests that the discovery has limited immediate implications for most people at risk of a heart attack.

But rare genetic variations often shine powerful spotlights on disease pathways, with profound results. The development of the cholesterol-lowering drugs called statins, which have transformed the treatment of heart disease, was propelled by knowledge gleaned from patients with a rare genetic abnormality.

There isn't any assurance that the new discovery will have a comparable impact, but the finding already is generating intense interest among genetics experts. Among other things, it will prompt an intensive search for other, more subtle variations in the gene that might explain differences in heart-disease risk in the broader population, says Craig Hanis, professor of human genetics and epidemiology at the University of Texas Health Science Center, Houston.

The MEF2A gene, discovered in the late 1980s by Eric Olson and his colleagues at the University of Texas Southwestern Medical Center, Dallas, controls the development of muscle tissue, including the muscle in the walls of coronary arteries. In particular, it is important for the formation of blood vessels in the embryo, Dr. Olson says. The new report suggests that the gene is also important in maintaining the integrity of blood vessels in adults, he adds.

The study at the clinic began in 2001 when a patient told his doctor there about his 10 siblings and their struggles with heart disease. He was referred to Dr. Topol and to researcher Qing Wang, who were working on a project to identify potential heart-attack genes. The patient and his family provided DNA samples that researchers analyzed in Dr. Wang's laboratory.

Each of the participating family members either smoked or had at least one other risk factor, such as high cholesterol or high blood pressure. Given that and their age when the disease struck -- early 60s for most of them -- it is possible to conclude that the patients would have suffered a heart attack anyway.

But as the entire genome of each family member was analyzed, a distinct pattern emerged, Dr. Topol says. "There was this hot spot that lit up on chromosome 15 only in people who have had the disease." There wasn't any signal at that spot from members without heart trouble. "That was the smoking gun," Dr. Topol says.

Further research established the presence of the gene in the coronary artery walls as well as the mutation itself, which involves a deletion of 21 units of DNA known as base-pairs and seven different amino acids associated with them. The researchers believe the missing amino acids resulted in a weakening of the inner lining of the coronary artery walls, leaving them susceptible to the formation of heart-attack causing deposits called plaques.

Dr. Topol says researchers have now analyzed the DNA of more than 50 family members, including one as young as 10 years old. They are beginning to use the findings to counsel those with the mutation to avoid smoking, follow healthy diets and exercise and keep cholesterol and blood pressure under control.

For 11 of the 13 family members with serious heart disease, the onset of symptoms happened like clockwork around the age of 61. For this specific family, and anyone who turns out to have the mutation, the hope is that the genetic information will encourage changes in living habits that will at least delay the consequences of disease until much later in life.

Write to Ron Winslow at ron.winslow@wsj.com¹

Updated November 28, 2003