Mutations in the APOB, LDLR, LDLRAP1, or PCSK9 gene cause familial hypercholesterolemia. Changes in the LDLR gene are the most common cause of this condition. The LDLR gene provides instructions for making a protein called a low-density lipoprotein receptor. This type of receptor binds to particles called (LDLs), which are the primary carriers of cholesterol in the blood. By removing LDLs from the bloodstream, these receptors play a critical role in regulating cholesterol levels. Some LDLR gene mutations reduce the number of low-density lipoprotein receptors produced within cells. Other mutations disrupt the receptors’ ability to remove low-density lipoproteins from the bloodstream. As a result, people with mutations in the LDLR gene have very high levels of blood cholesterol. As the excess cholesterol circulates through the bloodstream, it is deposited abnormally in tissues such as the skin, tendons, and coronary arteries.
Less commonly, familial hypercholesterolemia is caused by mutations in the APOB, LDLRAP1, or PCSK9 gene. Proteins produced from these genes are essential for the normal function of low-density lipoprotein receptors. Mutations in any of these genes prevent cells from making functional receptors or alter the receptors’ function. Hypercholesterolemia results when low-density lipoprotein receptors are unable to remove cholesterol from the blood effectively. Some people with familial hypercholesterolemia do not have a mutation in one of these genes. In these cases, the cause of the condition is unknown.
Both genetic and environmental risk factors play roles in familial hypercholesterolemia. Lifestyle choices including diet, exercise, and tobacco smoking strongly influence the amount of cholesterol in the blood and the risk of coronary artery disease. Additional factors that impact the outcome of the condition include a person’s gender, age, and health problems such as diabetes and obesity.
Familial hypercholesterolemia accounts for only a small percentage of all cases of high cholesterol. Researchers are working to identify and characterize additional genes that may influence cholesterol levels and the risk of heart disease in people with other forms of hypercholesterolemia.