Role of genes in CAD

While there are many risk factors for coronary artery disease that patients can control, they can’t change their genes – at least not yet. Scientists have identified more than 250 genes that may play a role in the development of CAD. Research has shown that atherosclerosis often begins in childhood with subtle damage to the interior lining of arterial walls (e.g., the endothelium). Studies have also shown that atherosclerosis is more widespread than was once thought. A person with atherosclerosis in their coronary arteries is more likely to have the condition in other arteries also. These findings suggest a genetic component to atherosclerosis, although researchers have yet to uncover the complex interaction between a person’s genetic make-up and their likelihood of developing coronary artery disease and atherosclerosis.

Some progress has been made, however, concerning the relationship between genes and cholesterol. Cholesterol is carried through the bloodstream by proteins called apolipoproteins. When these proteins wrap around cholesterol and other types of fats (lipids) to transport them through the bloodstream, the resulting “packages” are called lipoproteins. There are five different types of lipoproteins:

* High-density lipoproteins (HDL), which are associated with “good” cholesterol.

* Low-density lipoproteins (LDL), associated with “bad” cholesterol.

* Very-low-density lipoproteins (VLDL), which are associated with “very bad” cholesterol.

* Intermediate–density lipoproteins. Like VLDLs, these also carry both cholesterol and another type of fat (lipid) called triglycerides.

* Chylomicrons, which only carry a small percentage of cholesterol. Chylomicrons are mostly rich in triglycerides.

For more detailed information, see Cholesterol & Your Health.

The primary cholesterol-related genes that scientists are exploring as a means of better understanding and combating CAD include:

* Apolipoprotein A1 (APOA1). APOA1 is the major component of HDL, or protective cholesterol. Scientists have discovered that variations in the gene that codes for APOA1 can affect HDL levels, thus affecting overall risk for heart attack and stroke.

* CETP, or cholesterol ester transfer protein. This protein is involved in transforming cholesterol from the protective HDL form to the damaging LDL form. Research has shown that certain variations in the genes that code for CETP may result in higher HDL levels. Additionally, CETP is the target of newer drugs, which have not yet been approved, that seek to inhibit transformation of HDL into LDL cholesterol.

* LDL Receptor (LDLR). LDL receptors are present mostly in the liver cells, where they are responsible for recognizing LDL in the bloodstream and removing it. About one in every 500 people, however, has a mutation in the gene that controls the LDL receptors and inhibits their function, allowing LDL to build up in the blood. This condition is known as familiar hypercholesterolemia (FH). FH is the most widespread inherited cholesterol disorder, with affected individuals having cholesterol levels as high as 550 milligrams per deciliter. This is almost four times the desired level, thereby significantly increasing the risk for early heart attack, regardless of the presence of other risk factors. Researchers have also discovered that high-fat diets can also create subtle alterations in the LDLR gene even among people with normal LDLR genes. If too much dietary fat is present, too much LDL cholesterol is absorbed into the liver. In response, the liver cells repress the LDLR gene, which results in fewer LDL receptors and less LDL removed from the bloodstream. As a result, LDL levels rise in the bloodstream and can contribute to heart disease.

* Apolipoprotein E (APOE). Apolipoprotein E is a major component of VLDL. Variations in the gene that controls APOE can cause high levels of LDL to occur, especially in people who eat a high-fat, high-cholesterol diet.

* Apo(a). A gene that creates the Apo(a) protein, which combines with LDL cholesterol to form Lp(a), a new protein that affects the ability of the blood to clot (coagulation). High Lp(a) levels in the blood have been linked to the development of CAD and to increased heart attack risk.

* Apo(b). This gene controls the production of apo(b), another component of apolipoproteins and chylomicrons. Blood test that measure apo(b), or one of its products, apoB100, are considered a very accurate risk assessment for heart attack risk.

Other genes that are being investigated as to their impact on CAD include:

* Integrin (ITGB3). Another gene that affects coagulation, variations of ITGB3 have been found in a significant number of CAD patients.

* Elastin (ELN). The blueprint for a protein component of the elastic fibers found throughout the body. These fibers affect the elasticity of body tissue such as blood vessels. For instance, arteries deficient in elastin will often take a shape that inhibits the flow of blood and contributes to CAD. Elastin is lost as a part of the aging process.

* PTGIS. The blueprint for a protein (prostacyclin) that coats the inner layers of blood vessels, keeping blood from sticking and forming clots.

* ACE. While this gene is one of the most studied in regard to CAD, very little is known about its effect on heart disease. ACE is the blueprint for a protein that affects the heart, kidneys and arterial walls.