Gene study hunt finds new clue to premature heart attacks

November 26, 2001

DALLAS, Nov. 27 - In one of the largest genetic studies of its kind, researchers have discovered three previously unidentified genetic variants that may explain why some families are prone to premature heart disease, researchers report in today's issue of Circulation: Journal of the American Heart Association.

Investigators at 15 institutions used a technology called "high throughput" microarray genotyping to sift through 62 genes of 352 individuals with coronary artery disease and 418 individuals without. The culprit genes belong to the group of genes that regulate thrombospondin (TSP), a protein that helps blood clot.

"We've always been looking for the smoking-gun evidence for the genetic basis of early heart attacks, which is the worst kind of heart disease. You could say we stumbled into this thrombospondin story," says study chairperson Eric J. Topol, M.D., chairman of cardiovascular medicine at the Cleveland Clinic Foundation.

The investigators discovered distinctive variations in the genes of families with coronary artery disease, including one that may have a protective effect. Changes known as single-nucleotide polymorphisms (SNP) were observed in genes that produce different thrombospondin proteins. These proteins govern a number of factors associated with heart disease: new blood vessel growth, blood clotting, the blood vessel response to oxidized low-density lipoprotein cholesterol (LDL) and the ability of arteries to protect themselves from internal weakness.

In the families with coronary artery disease, at least two members had a heart attack or coronary revascularization at a young age - before age 45 in men and age 50 in women. Compared to the heart disease-free families, the affected family members were more likely to be male, older, diabetic, hypertensive and have a higher body mass index.

The variant identified as thrombospondin-4 (TSP-4) was associated with the strongest risk for heart attack - those with it had an 89 percent greater likelihood of having a heart attack. The TSP-2 variant was protective; individuals with it were 69 percent less likely to have a heart attack, says Topol.

Individuals with two copies of one of the variants, called the missense variant in thrombospondin-1, seemed to have both a much higher risk of early heart disease and the lowest levels of thrombospondin-1 in blood tests, the researchers found.

Individuals with variants of the TSP gene tended to have low levels of thrombospondin.

"The coincidence of finding an association with three distinct SNPs in thrombospondin genes and the functional correlation of low blood levels with the highest risk genotype for thrombospondin-1, indicates a potential biological link between thrombospondin variation and premature coronary artery disease. This warrants further study to validate the association and explain the biological mechanism," Topol says.

"This study is the largest genotyping of cardiovascular risk to date, and one of many approaches to unravel the most important cause of death and disability in our society."

The findings must be replicated and extended to determine the precise mechanism by which these gene variants and others may cause premature heart attacks, he says.

However, he notes, "The thrombospondin proteins play a critical role in vascular integrity and thrombosis and may play a role, if altered, in premature atherosclerosis and heart attack."

Genetic screening of the general population is not warranted at this time, he notes.
Other researchers are Jeanette McCarthy, Ph.D.; Stacey Gabriel, Ph.D.; David J. Moliterno, M.D.; William J. Rogers, M.D.; Kristin Newby, M.D.; Matt Freedman. Ph.D.; Jennifer Metivier, M.S.; Ruth Cannata, R.N., B.S.N.; Christopher J. O'Donnell, M.D., MPH; Kandice Kottke-Marchant, M.D., Ph.D.; Gurunathan Murugesan, Ph.D., Edward F. Plow, Ph.D.; Olga Stenia, Ph.D.; and George Q. Daley, M.D., Ph. D.

CONTACT: For journal copies only,
please call: (214) 706-1396
For other information, call:
Carole Bullock: (214) 706-1279
Bridgette McNeill: (214) 706-1135

American Heart Association

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