Genetic Detectives Find Source of Elevated Heart Disease Risk in Family With Healthy Total Cholesterol Level

For immediate release: November 14, 2003


Bill Seiler

[email protected] | 410-328-8919

Researchers at the University of Maryland School of Medicine have discovered two novel genetic defects, which contribute to extremely low levels of high-density lipoprotein (HDL), the "good" cholesterol. The discovery was made while studying a family with premature coronary disease even though individual total cholesterol levels were within the acceptable range.

The study results are published in the November 14, 2003, issue of Circulation Research, a journal of the American Heart Association, and are part of ongoing research at the University of Maryland on low HDL families.

One member of the family, a non-smoking man from Plattsburgh, New York, had a markedly reduced HDL level, 6 milligrams per deciliter (mg/dL) of blood, when the usual average is 45 mg/dL. He was successfully treated for a blocked heart artery with angioplasty at age 44. His highest untreated total cholesterol level was 194, a number that usually puts a person in a low risk category for heart disease. However, even before he was placed on cholesterol lowering statin therapy, his total cholesterol levels were often below 150, a level that has previously been viewed as protective against a heart attack.

"We used to believe that heart attacks do not occur when total cholesterol levels are under 150 mg/dL. However, recent studies suggest that despite healthy cholesterol levels, heart disease risk may still be increased if levels of HDL are too low, and there is early heart disease in the family," says study co-author Michael Miller, M.D., director of preventive cardiology at the University of Maryland Medical Center and associate professor of medicine at the University of Maryland School of Medicine.

"Our research underscores that family history is an extremely important part of the screening process to determine a person's risk for heart disease," notes Dr. Miller. "The average HDL level in men is about 45 mg/dL, and for women, about 55. If your HDL is 35, it's more likely to be the combination of genetic and environmental interactions. But if it's below 20, then there is a higher likelihood that there is a genetic problem."

Low HDL is the most common cholesterol abnormality in heart disease patients. It is defined as less than 40 mg/dL in men and less than 50 in women. According to Dr. Miller, low HDL is very common in the United States, affecting one in every three or four otherwise healthy adults. By contrast, what is termed "very low" HDL (less than 20 mg/dL) occurs in only one percent of the population.

Dr. Miller says family history is not included in national guidelines used to determine who might benefit from treatment for coronary disease. A formula, called the Framingham risk score, looks at five variables: high total cholesterol, age, smoking, blood pressure and low HDL. According to Dr. Miller, "If you have an abnormally low HDL with a normal cholesterol level, but you have a family history of coronary disease, that should be a red flag."

The researchers began their genetic detective work in 1995 by looking at two genes, known as apo A-I and LCAT, which frequently have defects responsible for low HDL levels. "We usually scan these genes first, and in some cases we sequence them to see if there is some sort of mutation that may be causing this low HDL syndrome," says Jeffrey Rhyne, M.S., a laboratory supervisor at the University of Maryland School of Medicine. "But we found nothing in the usual suspects."

The search for more suspects increased in 1999, when mutations in a gene called ABCA1 were first reported. This gene plays a role in the regulation of cholesterol and HDL metabolism. It may also help prevent atherosclerosis, a plaque forming process in the inner lining of an artery, reducing the flow of blood through the artery. Plaques can rupture and block blood flow, leading to a heart attack or stroke.

The researchers found two mutations in the Plattsburgh man's gene, one inherited from his mother's side of the family, the other inherited from his father's side. One of the mutations interfered with the process called "gene splicing," a process that all genes must undergo to be put together correctly. The lack of normal splicing resulted in a malfunctioning gene, because one section of the gene had been omitted.

One mutation occurred in a region of the gene not previously known to be involved in gene splicing. "The ABCA1 gene has 50 segments, so it takes a lot of time to dig through and see if we can find something," says Rhyne. "The different segments are called exons. In this particular case, we found a mutation in exon 41 and also around exon 48."

"Having either of these defects would lower the HDL 30 or 40 percent below normal, putting him in the 20-to-30 mg/dL range," says Dr. Miller. "But having both defects caused an extremely low level of 6 mg/dL HDL." Several of the man's siblings also have both defects. One brother has an HDL of 8, another brother's HDL is 12 and a sister's HDL level is 17.

Dr. Miller says people with very low HDL levels can take some steps to reduce their risk of heart disease. He says exercise and niacin can both raise the HDL, and a good diet can reduce LDL, the so-called "bad" cholesterol. "Our recommendation is that people with high LDL try to be active, maintain a diet low in saturated fat and eliminate all trans fats in the diet," says Dr. Miller. He adds that medications called statins can also help reduce LDL.

"Statins are great LDL lowering medications because they reduce the progression of heart disease," says Dr. Miller. "However, to reverse heart disease, the levels of HDL and/or its protective function need to be enhanced. This is a very exciting area of research which is now, finally, capturing a great deal of attention in the field of coronary disease prevention," according to Dr. Miller.

Sueng Ho Hong, Ph.D., formerly of the University of Maryland School of Medicine, also co-authored the study.

A National Institutes of Health grant, an American Heart Association Grant-In-Aid, and a Veterans Affairs Merit Award supported the study.


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