Q. Define Thrombospondin Polymorphisms

Thrombospondin polymorphisms may present an initial insight into our understanding of the genetic contribution to coronary atherosclerosis. Although a familial linkage for CAD is well documented, little is known about the causative factors leading to premature events in such families.

Thrombospondins are a family of glycoproteins that play a pivotal role in cell adhesion, vascular integrity, and thrombosis. Variations in thrombospondin genes have been linked to premature atherosclerosis and MI and may provide an example of how genetic polymorphisms can lead to the development of coronary disease.

The etiology of Coronary Artery Disease (CAD) is multifactorial. Coronary atherosclerosis is a complex process with inflammation characterized by the accumulation of lipid, macrophages and smooth muscle cells in intimal plaques in the large and medium-sized epicardial coronary arteries. The vascular endothelium plays a critical role in maintaining vascular integrity and homeostasis. Mechanical shear stresses (e.g. from hypertension), biochemical abnormalities (e.g. elevated and modified Low density lipoprotein (LDL), diabetes mellitus, elevated plasma homocysteine, immunological factors (e.g. infection such as Chlamydia pneumoniae and Helicobactor pylori) and genetic alteration may contribute to the initial endothelial ‘injury' or dysfunction, which is believed to trigger atherogenesis. The development of atherosclerosis follows the endothelial dysfunction, with increased permeability to and accumulation of oxidized lipoproteins, which are taken up by macrophages at focal sites within the endothelium to produce lipid-laden foam cells. Macroscopically, these lesions are seen as flat yellow dots or lines on the endothelium of the artery and are known as ‘fatty streaks'. The ‘fatty streak' progresses with the appearance of extracellular lipid within the endothelium (‘transitional plaque'). Release of cytokines such as platelet-derived growth factor and transforming growth factor-β (TGF-β) by monocytes, macrophages or the damaged endothelium promotes further accumulation of macrophages as well as smooth muscle cell migration and proliferation. The proliferation of smooth muscle with the formation of a layer of cells covering the extracellular lipid, separates it from the adaptive smooth muscle thickening the endothelium. Collagen is produced in larger and larger quantities by the smooth muscle thickening in the endothelium and the whole sequence of events cumulates as an ‘advanced or raised fibrolipid plaque'. The ‘advanced plaque' may grow slowly and encroach on the lumen or become unstable, undergo thrombosis and produce obstruction (‘complicated plaque').