Familial hypercholesterolemia: genetic predisposition to atherosclerosis

MedSurg Nursing, August, 2004 by Mary B. Engler

Cardiovascular disease remains the leading cause of death in the United States, with an average one death every 34 seconds. More than 64 million Americans have one or more types of cardiovascular disease that will have an estimated direct and indirect cost of $368.4 billion in 2004 (American Heart Association, 2004). By the year 2020, cardiovascular disease is expected to become the primary cause of death throughout the world (International Atherosclerosis Society [IAS], 2003).

As a result of the atherosclerotic process, cardiovascular disease is due to the interaction between environmental risk factors, such as diet, physical inactivity, smoking, and an individual's genetic makeup. Hundreds of genes are believed to be involved in the process of atherogenesis and the susceptibility to cardiovascular disease. These include genes that regulate lipid metabolism, inflammatory and immune responses, endothelial function, and coagulation. Other genes involved in obesity, insulin resistance, diabetes, elevated homocysteine levels, and hypertension have been identified, but their mechanisms in the atherosclerotic process are not well understood (Lusis, 2003). The genes involved in lipid metabolism have been extensively studied and identified, specifically the gene coding for the low-density lipoprotein (LDL) receptor.

Pathophysiology

Many experimental, clinical, and epidemiological studies have demonstrated the strong association between increased levels of LDL-cholesterol (LDL-C) and coronary heart disease (IAS, 2003). Lowering total cholesterol and LDL-C reduces the risk for coronary heart disease, as demonstrated in major clinical trials with statin drugs or the HMG-CoA reductase inhibitors (lovastatin [Mevacor[R]], pravastatin [Pravachol[R]], simvastatin [Zocor[R]]) (Downs et al., 1998; Lipid Study Group, 1998; Sacks et al., 1996; Shepherd et al., 1995; The Scandinavian Simvastatin Survival Study [4S] Group, 1994). Approximately 70% of plasma cholesterol is carried by LDL-C particles (Gotto, 1999). Concentrations of circulating LDL-C are closely linked to atherogenesis and are regulated by a balance between the rates of its synthesis and removal. Hepatic LDL receptors remove most of the LDL-C from the plasma. However, increased LDL-C concentrations in the plasma can lead to LDL-C deposition in extra-hepatic tissues, including the arterial wall. Early events in the process of atherosclerosis are characterized by recruitment of leukocytes and the production of pro-inflammatory cytokines, as well as the accumulation of LDL-C and its subsequent oxidation within the intimal layer of the arterial wall.

Hypercholesterolemia is one of several cardiovascular risk factors that impairs endothelial function. Dysfunctional endothelium promotes lipid and cell permeability, oxidation of lipoproteins, inflammation, proliferation of vascular smooth muscle cells, deposition and lysis of extra-cellular matrix, platelet activation, and thrombus formation. Cytokines are produced and adhesion molecules (selectins, vascular cell adhesion molecules [VCAM], intracellular adhesion molecules [ICAM] are expressed by the dysfunctional endothelium, which promotes leukocyte adhesion and infiltration into the arterial wall (Fuster, Corti, Fayad, & Badimon, 2003).

Once LDL-C has passed through the endothelium into the subendothelial space due to enhanced lipid permeability, oxidation of LDL-C occurs and a number of chemotactic factors are also released. Inflammation is a key process involved in all stages of atherosclerosis. Monocytes adhere and infiltrate into the subendothelial space, becoming macrophages which engulf oxidized LDL-C particles. Foam cells accumulate to form a fatty streak in the arterial wall. With time, the fatty streak progresses to an advanced lesion with a fibrous cap composed of collagen and a lipid core. The lumen of the vessel becomes occluded and the vulnerable plaque may eventually rupture due to weakening of the fibrous cap by matrix metallo-proteinases (proteolytic enzymes), leading to an acute coronary event (Fuster et al., 2003).

Familial hypercholesterolemia, a genetic disorder, is caused by a mutation in the gene for the LDL receptor. This mutation can prevent the synthesis of LDL receptor proteins, or it can cause the formation of a defective LDL receptor that can't bind or ingest LDL into the liver cells (see Figure 1). This leads to abnormal clearance of LDL by the liver and elevated serum cholesterol levels. Premature atherogenesis and coronary heart disease are eventual outcomes. Familial hypercholesterolemia was the first monogenic disorder shown to cause elevated cholesterol levels (Nabel, 2003). The gene for the LDL receptor is found on chromosome 19, and over 700 mutations have been identified in patients with this disorder (Durrington, 2003).

[FIGURE 1 OMITTED]

Five classes of functional LDL receptor defects result from mutations in this gene (Benlian, 2001). Class 1 defects represent an absence of receptor synthesis due to an absence of mRNA or protein. Class 2 defects are characterized by defective receptor maturation or transport within the endoplasmic reticulum and Golgi apparatus. Class 3 defects represent defective binding of receptors to LDL-cholesterol. Class 4 mutations produce endocytosis-defective receptors, which in effect disable entry of LDL into the cytoplasm for further processing. Class 5 defects result in the recycling of defective LDL receptors instead of normal ones after endocytosis. Those affected individuals carrying class 1 mutations with no production of LDL receptors typically have higher plasma LDL levels and earlier, more severe coronary heart disease. The identification of genetic mutations in the LDL receptor has been critical to the understanding of lipid metabolism and to the development of targeted interventions, such as, lipid-lowering therapy with statin drugs (Benlian, 2001).