Genetic Involvement in Heart Disease - II

Before we talk about this disorder, I would like for you to first visualize a lock and key, or a ball and glove. In both cases there is a fit, a direct connection between the 2 objects. These very simple images serve to illustrate a very intricate cellular mechanism, which when faulty, can lead to a significantly increased risk of early coronary artery disease.

For most individuals, the risk of heart disease is multifactorial, meaning a combination of genetic and environmental influences. The most common environmental influences include smoking, a high cholesterol diet, and an inactive lifestyle. However, for approximately 1 in 500 individuals, there is a strong genetic component in the disease. In 1974, Goldstein and Brown identified the genetic and molecular cause for early onset coronary disease in many families. Much like the ball and glove analogy, Goldstein and Brown described the role of cell surface receptors in cholesterol metabolism.

Normally our cells receive cholesterol either through natural body synthesis or through the diet. The pattern for cholesterol metabolism requires that plasma cholesterol be recognized by and attached to receptors on the cell’s surface (ball and glove fit). The cholesterol is then transported into the cell for processing. This cholesterol uptake process is a precise feedback mechanism designed to regulate cholesterol levels and requires normal gene functioning.

Familial hypercholesterolemia (FH) is a disease characterized by exceedingly high plasma cholesterol levels due to defective LDL (low density lipoprotein) cellular receptors. FH is inherited as an autosomal dominant trait involving a gene located on chromosome 2. The disease is apparent earlier and more severely in the individual carrying 2 mutant genes (homozygote) versus the heterozygote. More than 400 different mutations have been identified, resulting in 5 different classes or causes for the disease. In all instances, the normal functioning of the LDL receptor or cholesterol processing is compromised. Treatment for FH involves dietary restriction of cholesterol and the use of statin drugs to prevent or deter complications.