Genetic Make-Up May Determine Response To Cholesterol-Lowering Drugs

March 20, 1998

SANTA FE, N.M., March 20 -- Genetic make-up may significantly influence how a person responds to a cholesterol-lowering drug, according to researchers who presented their findings at the American Heart Association's epidemiology and prevention conference today.

"Not everyone benefits from lipid-lowering drugs. There are genetic variations that appear to make some individuals more responsive and others less responsive," says Maren Scheuner, M.D., M.P.H., director of GenRISK, a clinical genetic risk assessment program at Cedars-Sinai Medical Center and assistant professor of medicine at University of California School of Medicine, Los Angeles.

"This study may help us determine who may or may not benefit from this particular form of the cholesterol-lowering drug Lovastatin. It may also be an important step in our ability to stratify individuals based on their genetic risk of cardiovascular disease," she says.

Scheuner and her colleagues studied a group of 485 individuals who had undergone coronary artery bypass surgery, which involves using a blood vessel graft to bypass blockages in the coronary arteries that carry blood to the heart. Patients were given either a high or a low dose of the cholesterol-lowering drug to determine which dose was most effective in helping prevent the development of new fat-rich blockages in grafted blood vessels. High blood levels of cholesterol, particularly "bad cholesterol," help initiate these obstructions or atherosclerosis, impairing blood flow to the heart.

The researchers also conducted DNA studies to identify variations in the gene for lipoprotein lipase, an enzyme that plays a role in cholesterol metabolism. Other scientists have found the lipoprotein lipase gene is tied to elevated cholesterol, insulin resistance, and severity of coronary artery disease.

Four to five years after entry into the clinical trial, researchers used angiography, an X-ray, to determine whether new blockages had developed in the grafts. Higher doses resulted in fewer new blockages in grafts than lower doses. However, not everyone benefited from the drug.

Scheuner identified a variant of the gene that was associated with unresponsiveness to treatment. Individuals in the study who had two copies of the gene variant -- about 8.5 percent of the total group -- were about twice as likely to have progression of atherosclerosis as those who do not have any copy of this variant. This suggests that one in 12 individuals who take this drug may not benefit, she says.

"So having this genetic information may help us better understand what causes unresponsiveness in these individuals and as a result help identify better, more targeted therapies," she says.

The study was presented at the American Heart Association's 38th Annual Conference on Cardiovascular Disease Epidemiology and Prevention.

Co-authors are Huiying Yang, M.D., Ph.D.; Kent Taylor, Ph.D.; Zhiming Li; Talin Harintunians; Richard Gray, M.D.; Prediman K. Shah, M.D.; James Forrester M.D.; and Jerome Rotter M.D.
Media advisory: Dr. Scheuner can be reached at (310) 967-1663 or 1664. (Please do not publish telephone numbers.)

NR 98-4865(Epi98/Scheuner)

American Heart Association

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