Gene variant increases heart disease risk, even when cholesterol is normal

November 06, 1999

ATLANTA, Nov. 7 -- A gene already implicated in high cholesterol may pose yet another risk for heart disease, according to a study presented today at the American Heart Association's Scientific Sessions.

Apolipoprotein E is a key protein involved in the transport and disposal of cholesterol in the body. Sitting on the surface of circulating blood-fat particles, apo E normally binds to liver cells, to help rid the body of cholesterol. There are three variants of apo E.

Lead investigator of the study, Angelo Scuteri, M.D., Ph.D., of the National Institute of Aging in Baltimore, Md., says research suggests that one of the variants, apoE-4, raises levels of total cholesterol and "bad" low-density lipoprotein, or LDL. Too much cholesterol in the blood can block blood vessels, setting the stage for a heart attack or stroke.

To determine if the apoE-4 variant was associated with heart disease, Scuteri and his colleagues studied 731 healthy men and women in the Baltimore Longitudinal Study of Aging, a study that began in 1958 and involved individuals ranging in age from 21 to 96. The study participants underwent physical, physiological and psychological exams every two years for 17 years. The study included men and women age 50 or older who had no apparent signs of heart disease. More than half (57 percent) of the participants were men.

Gene testing revealed that 200 of the 731 individuals had the apoE-4 gene, and they also were more likely to have a "coronary event" later in life than those without the variant--roughly 20 percent versus 13 percent in the non-mutation group. Coronary events were defined as angina (chest pain), heart attacks or dying from heart attack or another form of coronary heart disease.

A surprising finding was that individuals with apoE-4 still had an increased risk of heart disease, even if their cholesterol levels and blood pressure were normal.

Overall, there were 104 coronary events among the study group. Because most of those events were angina (severe chest pain due to blockages), Scuteri says a separate analysis was done for heart attacks and deaths. The results were similar to the original finding that the apoE-4 gene variant significantly increases an individual's risk of heart disease.

"Prior studies suggested that the major effect from apoE-4 was an increase in cholesterol levels. We showed that the association with heart attack was found even when an individual's cholesterol level was normal. So there may be another, yet to be determined, explanation for the adverse effects of apo-E4," says Scuteri.

"It is interesting that our study shows an association between apo-E4 and the incidence of coronary events that is independent of cholesterol levels. This means that the apo-E4 gene provides information about overall cardiovascular risk that is separate from cholesterol," he says.

One aim of the study of genetic markers in cardiovascular disease is to possibly tailor the treatment according to gene type. There is no data to support the hypotheses that the apo-E4 gene may predict how an individual will respond to cholesterol-lowering medication. However, the apo-E4 gene has been reported to predict the cholesterol response to estrogen replacement therapy in post-menopausal women.

Although researchers stress that their findings are preliminary, they say the apoE-4 gene may emerge as an important gene target for treating heart attacks. "Our goal is to provide doctors with blood tests or markers that will enable them to predict and treat heart disease earlier. Since we cannot change the genes, individuals with apoE-4 may require earlier treatment," he says. "But we cannot consider our data conclusive at this point. It needs to be confirmed in other population groups."

Co-authors are Angelo J.G. Bos, M.D., Ph.D.; Alan B. Zonderman, Ph.D.; Larry J. Brandt, Ph.D.; Edward Lakatta, M.D. and Jerome L. Fleg, M.D.

American Heart Association

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