Obscure gene family linked to early heart disease

NEW ORLEANS, Louisiana (Reuters) -- Researchers Sunday said they had identified mutations in three related genes that significantly increase the odds of a person getting heart attacks and developing diseased coronary arteries before age 50.

Dr. Eric Topol, chairman of the department of cardiology at the Cleveland Clinic Foundation, said a commercial diagnostic test for the mutated genes could be available within two years and help doctors assess a person's hereditary risk of developing premature heart disease.

Topol said his study was based on collaboration at 15 medical centers in the United States, the Whitehead Institute at the Massachusetts Institute of Technology and gene-hunting biotech firm Millennium Pharmaceuticals Inc. of Massachusetts.

Topol said Millennium had patented the mutant genes and would have commercial rights to any diagnostic tests based upon them.

His research group identified 420 families, composed of 1,366 patients, in which at least two siblings had premature coronary artery disease -- defined as heart attack or hardening of the arteries before age 45 for men and age 50 for women.

DNA of more than 340 of the patients who had been diagnosed with a heart attack or diseased arteries was compared with a control group of subjects with no known heart disease, with results adjusted for age, gender, weight and blood pressure.

"Our goal was to discover which genes might be causing such serious heart problems in such a young population, many of whom were under age 40," Topol said in an interview at the annual scientific sessions of the American Heart Association being held here.

Using scanners, The Whitehead Institute scrutinized about 60 genes, including ones that cause blood to clot and that create the "bad" LDL form of cholesterol and "good" HDL form of cholesterol.

Topol said researchers were surprised that only three genes emerged as significant and that all are members of the same obscure family of thrombospondin genes -- which create proteins involved in blood vessel structure and function.

"Thromobospondins do many things. They regulate blood clotting and the way cells attach to each other," said Topol. He added that all people have four different thrombospondin genes that each produce a distinct protein vital for survival.

Researchers found that patients with premature heart disease had the same inherited mutations in one or more of three of the genes -- TSP-1, TSP-2 and TSP-4.

The rarest and most worrisome of the mutations, or single nucleotide polymorphisms (SNPs), was TSP-1. Topol said it is seen in less than one percent of the general population.

"If you have the TSP-1 mutation, it appears you have a 10-fold higher risk of premature heart attack before age 40. That looks like a really bad gene to have," said Topol, who noted that larger studies would be needed to confirm the importance of all the mutant genes.

"There is a three-fold risk of early heart disease if you have the TSP-2 mutation. And there is a two-fold increase in risk if you have the TSP-4 variation, a mutation which also significantly increases your risk of stroke," Topol said.

Researchers also found that patients with the gene mutations had smaller amounts of thrombospondin protein in their bloodstream, another cause for concern.

Topol said the three gene mutations are the first genetic markers for risk of premature heart disease and could eventually also indicate increased risk of developing heart disease later in life.

"None of us suspected that thrombospondin would be so important before we did this study. Until now, there have been no genes that have been clearly identified for atherosclerosis (clogged arteries), the number 1 killer in Western society," the Cleveland researcher said.

He speculated that a handful of other gene families may also be linked to heart disease in the next five years, all of which will join the thrombospondin mutations as reliable predictors of disease once diagnostic tests are created.

Indeed, in another study presented Sunday, researchers described a different genetic marker they said showed promise for use in screening for heart disease risk.

Dr. Julian Halcox, a researcher with the National Heart, Lung and Blood Institute, said different versions of the gene that makes nitric oxide may program blood vessels to release more or less nitric oxide than other forms.

Nitric oxide is produced by the inner lining of the blood vessels called the endothelium and plays a key role in controlling blood pressure. It is needed to dilate, or open up, blood vessels when blood flow increases, such as during physical exercise.

Copyright 2000 Reuters. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

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American Heart Association
NHSA - National Heart Savers Association
AMA - Heart Attack

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