Obscure gene family linked to early heart disease

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 youhave 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 genemutations had smaller amounts of thrombospondin protein in their bloodstreams, 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 thrombospondins 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 One 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.