Even modest reductions in low-density cholesterol early in life significantly reduce risk for coronary heart disease, according to an article in the March 23 issue of the New England Journal of Medicine.

Researchers had learned that people with certain variations in the PCSK 9 gene produce lower levels of low-density lipoprotein cholesterol and they are significantly less likely to develop coronary heart disease later in life.

Based on 15 years of follow-up of more than 12,000 multiethnic American adults ranging in age from 45 to 64 years, researchers found that people who had cholesterol-lowering genetic variations that decreased their low-density cholesterol level by about 40 milligrams per deciliter were eight times less likely to develop coronary heart disease than those without the variations. People with genetic profiles that reduced their low-density cholesterol by about 20 milligram per deciliter from average had a two-fold reduction in heart disease.

“These data indicate that a moderate, life-long reduction in low-density cholesterol is associated with substantial reduction in the incidence of coronary events, even in populations with a high prevalence of other cardiovascular risk factors,” said Helen Hobbs, MD, the study’s senior author, director of the Eugene McDermott Center for Human Growth and Development and an investigator in the Howard Hughes Medical Institute at UT Southwestern.

Hobbs coauthored the study with Dr. Jonathan Cohen, professor of internal medicine and researchers from the UT Health Science Center in Houston and the University of Mississippi Medical Center in Jackson.

Scott Grundy, MD, director of the Center for Human Nutrition at UT Southwestern, served as chairman of the National Cholesterol Education Program’s Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, which in 2001 set guidelines for the clinical use of cholesterol-lowering medications to reduce the risk of cardiovascular disease. “This study demonstrates the great importance of high blood cholesterol in causing coronary heart disease,” said Grundy.

“It also shows the benefit of maintaining a low cholesterol level throughout life. The foundation for keeping low blood cholesterol is a reduced intake of saturated fats and cholesterol and maintaining a desirable body weight. But in some people it may be necessary to add drugs to reduce cholesterol levels. Fortunately, newer cholesterol-lowering drugs have been developed that are both effective and safe for most people.”

Previous research had established that people with a high level of low-density cholesterol in their blood are at greater risk of developing coronary heart disease. The present study further documents that life-long reductions in low-density cholesterol can actually help prevent heart disease.

The new findings are based on data obtained from subjects drawn from the Atherosclerosis Risk in Communities Study (ARIC), which tracked the health of participants from four communities in Mississippi, Minnesota, North Carolina and Maryland for 15 years, beginning in 1987. Researchers analyzed blood samples from those participants to determine who carried the cholesterol-lowering genetic variations. The researchers then tracked the subjects’15-year health history and found the association between lower long-term LDL levels and lower risk of heart disease.

The PCSK9 gene produces an enzyme that normally controls the number of low-density lipoprotein receptors lining the surface of liver cells. These receptors bind low-density cholesterol and remove it from the blood. The researchers had previously found that genetic mutations that inactivate PCSK9 result in lower levels of the PCSK9 enzyme, leading to higher levels of receptors. By increasing the amount of cholesterol removed in the liver cells, low-density cholesterol levels were lower in the blood of people with the mutations.

High levels of PCSK9 tend to raise blood concentrations of low-density cholesterol. Currently statins are the standard to lower low-density cholesterol in patients. However, statin treatment may increase production of the PCSK9 enzyme, which in turn may limit the effectiveness of these drugs. Developing new therapies that inhibit PCSK9 enzyme activity not only should lower low-density cholesterol levels, but in addition might enhance effectiveness of statins.