Familial Hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C), often called “bad” cholesterol, from birth. This inherited condition impacts the body’s ability to process cholesterol effectively.
Understanding Familial Hypercholesterolemia
Familial Hypercholesterolemia is a lifelong condition, distinct from high cholesterol levels caused by diet or lifestyle. Individuals with FH are born with elevated LDL-C levels due to an impaired mechanism for cholesterol processing. This defect means the body struggles to remove LDL cholesterol from the bloodstream, leading to its accumulation.
FH affects about 1 in 200 to 1 in 250 people in most countries, making it a common inherited condition. If left unaddressed, this elevated cholesterol contributes to plaque buildup in the arteries, which can lead to an increased risk of coronary heart disease at an early age. Untreated FH can elevate the risk of developing heart disease by as much as 20 times compared to the general population.
The Genes Behind Familial Hypercholesterolemia
Familial Hypercholesterolemia is primarily linked to mutations in specific genes. The most common cause involves the LDLR gene, which provides instructions for creating the low-density lipoprotein receptor. This receptor protein is on the surface of cells, particularly liver cells, and binds to LDL particles, moving them inside the cell for processing.
Other genes implicated in FH include APOB, PCSK9, and LDLRAP1. The APOB gene produces apolipoprotein B-100, a protein that is part of the LDL particle and acts as a binding partner for the LDL receptor. The PCSK9 gene provides instructions for a protein that regulates the number of LDL receptors on cell surfaces. The LDLRAP1 gene is involved in making a protein that helps facilitate the movement of LDL receptors and their bound LDL particles from the cell surface into the cell.
How Genetic Mutations Lead to High Cholesterol
Mutations in the LDLR gene can lead to a reduced number of LDL receptors or receptors unable to effectively remove LDL from the blood. When the LDL receptor is faulty or insufficient, LDL particles cannot be absorbed by liver cells, causing them to accumulate in the bloodstream. Over 2,000 different mutations have been identified in the LDLR gene, each potentially disrupting the receptor’s ability to bind, internalize, or recycle.
Mutations in the APOB gene prevent LDL particles from properly attaching to their receptors on cell surfaces. This impaired binding means fewer LDLs are cleared from the blood, resulting in higher cholesterol levels. For PCSK9, “gain-of-function” mutations enhance the PCSK9 protein’s activity, leading to accelerated breakdown of LDL receptors. With fewer receptors, the liver’s capacity to remove LDL cholesterol from circulation is diminished, contributing to its buildup. LDLRAP1 gene mutations result in a nonfunctional protein that impairs the transport of LDL receptors and their bound LDLs into cells, particularly liver cells, even if receptors can still bind to LDL normally.
Inheritance Patterns of FH
Familial Hypercholesterolemia often follows an autosomal dominant inheritance pattern, particularly for forms linked to LDLR, APOB, or PCSK9 gene mutations. This means a person only needs to inherit one altered copy of the gene from an affected parent to develop the condition. Individuals inheriting one mutated copy have heterozygous FH (HeFH), which is the more common type.
If an individual inherits two altered copies of the same gene, one from each parent, they have homozygous FH (HoFH), a much rarer and more severe form. HoFH can result in extremely high LDL cholesterol levels, sometimes three to six times higher than normal, and can lead to aggressive narrowing of blood vessels starting early in life. A less common form of FH, caused by LDLRAP1 gene mutations, is inherited in an autosomal recessive pattern, meaning two altered copies of the gene are needed for the condition to manifest.