Study Clarifies Heredity and Heart Disease Link

Times Medical Writer

Southern California scientists have taken a major step toward eventually understanding how heredity plays an important role in making an individual susceptible to heart disease.

The researchers, from UCLA’s Institute of Molecular Biology, Wadsworth Veterans Administration Medical Center and the City of Hope in Duarte, have succeeded in cloning the gene that determines the characteristics of the lipid-protein compound that delivers the bulk of cholesterol to body cells.

A large amount of evidence suggests that cholesterol is involved in atherosclerosis, the disease that results in fatty material becoming deposited on the walls of arteries, causing them to narrow and predispose the individual to a heart attack or stroke.


Controlling Cholesterol Intake

Controlling the dietary intake of cholesterol is a major method of preventing atherosclerosis. But scientists have long been struck by the fact that some Americans die of a heart attack in their 30s or 40s, while others live well into their 80s--in some cases despite unhealthy life styles.

It has been easy to speculate that differences in the genetically controlled ability to handle cholesterol is the explanation, but researchers have very little specific knowledge about the nature of these differences.

The new work, published today in the current issue of the Proceedings of the National Academy of Sciences, means that scientists now have an important new tool to help them work out the genetics of susceptibility for at least some groups of people, according to the researchers.

In a recent interview, Drs. Aldon Lusis, Renee LeBoeuf, Verne Schumaker, Michael Schotz and John Elovson explained the significance of their work.

Cholesterol is an essential ingredient for cells to make new membranes and for the manufacture of various hormones, including the male and female sex hormones. It is transported through the body inside packets known as lipoproteins, which are round balls of cholesterol in a protein coating.

Two of the several forms of cholesterol are known as low-density lipoprotein and high-density lipoprotein. A few years ago medical researchers learned that the ratio of these two types of cholesterol in the blood appears to be an important indicator of the individual’s chances of having a heart attack.

The presence of too much low-density lipoprotein, the researchers believe, is bad because it seems to mean a high susceptibility to heart disease. But a large amount of high-density lipoprotein is considered good because those people seem to be protected from coronary disease.

Mutations of Normal Gene

The gene cloned by the Southern California scientists controls the makeup of a protein called apo B that coats those low-density lipoproteins that are the body’s principal carriers of the “bad” cholesterol. The scientists are now in the process of learning how to identify individuals in whom mutations of the normal apo B gene causes those people to have an excessive amount of low-density lipoproteins, which leads to atherosclerosis.

Cells that have a need for cholesterol obtain it by making proteins called receptors that are attached to the cells’ outer coats. The receptors are designed to attract the lipoprotein packets passing by in the bloodstream. One of these receptors is designed specifically to attract the apo B protein on the surface of the low-density lipoprotein packets.

In some individuals, medical researchers believe, the transfer of the low-density lipoproteins from bloodstream to cell does not take place due to a defect in the receptor. In other individuals, the problem may be due to defects in the apo B protein that prevent low-density lipoproteins from becoming attached to the cell and entering it.

This results in an accumulation of low-density lipoproteins in the blood, which in turn places the individual at increased risk of developing atherosclerosis.

Numerous Mutations

Defects in the protein coating of low-density lipoproteins can be the result of mutations in the apo B gene. The researchers believe that in the general population there are numerous mutations that affect different aspects of low-density lipoprotein uptake by cells, and that all of these mutations can result in high blood cholesterol levels.

They are now trying to identify all of the different mutations.

Medical researchers have known for some time of the existence of individuals with cholesterol levels that are many times above normal and who die of heart attacks as early as in their teens. They are the offspring of parents who each have a genetic defect that affects the ability of cells to take up cholesterol from the bloodstream.

But, according to the researchers, a far greater percentage of the population has less extremely elevated cholesterol levels that may be hereditary or may be the result of unhealthy life style.

“We can’t say now which is hereditary and which is environmental, but atherosclerosis is to a large extent hereditary,” said Schumaker, the VA hospital researcher. “Apo B plays a central role. It is the sole protein in low-density lipoprotein. Until now we could not examine its genetics and biochemistry.”

More Studies Planned

Other researchers soon plan to study the apo B genes of the families of people with varying cholesterol levels. Because it is possible to distinguish the patient’s apo B genes according to which parent contributed which gene (every individual has two, one from each parent), the investigators said it will be possible to identify the genes that are associated with high and low cholesterol levels.

Regardless of the important role played by genetics, the scientists said they are convinced that people without major defects probably could largely overwhelm the genetic factor by strict adherence to the life style characteristics now advocated by most doctors--quit smoking, follow a low cholesterol diet, get adequate exercise and keep their blood pressure under control.