ABSTRACT
The study of genetic variants has been instrumental in the elucidation of many biological processes and biochemical pathways. In the field of atherosclerosis and lipid metabolism, a classic example is the identification of the low-density lipoprotein (LDL) receptor in familial hypercholesterolemia patients in which a genetic defect in the synthesis of the receptor results in the characteristic high LDL cholesterol levels and premature atherosclerosis [1]. In the general population, however, atherosclerosis is not a monogenic disorder as seen in familial hypercholesterolemia but rather a consequence of the interaction of numerous genetic and environmental factors, each exerting a positive or negative influence on susceptibility to the disease. Atherosclerosis can be considered to result from chronic injury to the arterial wall that is often initiated by hypercholesterolemia [2]. Cholesterol-rich lipoproteins derived from the plasma may become modified through oxidation and subsequently retained in the arterial wall. The accumulation of lipoproteins triggers an inflammatory response leading to endothelial cell activation and attraction of blood monocytes, which may pass into the artery wall and differentiate into macrophages. The macrophages express receptors that recognize modified lipoproteins and accumulate lipoprotein-derived cholesterol
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in the cytoplasm to produce ‘‘foam cells’’ that are characteristic of the early atheromatous lesion, known as a fatty streak. Progression of the lesion involves proliferation of arterial smooth muscle cells and death of foam cells with deposition of their cholesterol contents extracellularly. These events produce a more advanced lesion in which a cholesterol-rich core is covered by a fibrous cap composed of smooth muscle cells. Eventually, the surface of the lesion may rupture to expose the subendothelial layer and potentially initiate a thrombotic event leading to tissue ischemia such as an acute myocardial infarction.
