Monday, January 19, 2009


Atherosclerosis is a disease more commonly referred to as a 'Hardening of the arteries' (1), and is the major cause of morbidity and mortality in the western world (2). It is believed to be a multifactorial process, which can in some cases start in utero (3). Patients with atherosclerosis represent a heterogenous group of individuals, with diseases that progress at significantly different rates and in distinctly different patterns (5). It is described by the deposition of fatty material (atherosclerotic plaques) in, not on, arterial vessel walls - due to an excess in-flow of cholesterol. This can lead to occlusion of the artery - in most cases this occurs due to a sudden rupturing of the plaque that triggers the emergence of a blood clot/thrombus that blocks blood flow (as oppose to direct occlusion by the plaque) leading to complications such as strokes or heart attacks (1/4).

There are many risk factors for this disease: diet and lifestyle (environment) works synergistically with genetic factors predisposing to or protecting from the disease. Understanding the complexity and functional relevance of these risk factors especially the genetic factors can improve the early detection, management and prevention of this disease.
This essay will review some of these genetic factors (both predisposing and protecting) and discuss their contribution to the risk of developing Atherosclerosis.

Predisposing factors:
There have been many predisposing factors discovered using clues from the pathology of the disease including genes/proteins associated with blood lipids, endothelial cell changes (lipid deposition), macrophage responses, inflammation, oxidative damage, vascular repair control, thrombosis and diabetes/obesity (1).

Blood lipids: One of the most important risk factors for atherosclerosis is dyslipidemia (quantitative and qualitative changes in plasma levels of lipids and lipoproteins), (3). Atherogenic dyslipidemia has been genetically linked, is characterized by increased plasma triacylglyceride and apolipoprotein (apo) B levels, low HDL concentrations and the development of small dense LDL particles (8), and predisposes for atherosclerosis. HDL in particular is very important in the reverse cholesterol transport (RCT) pathway which is the major protective system against atherosclerosis (7), (clears excess cholesterol from arterial cell walls (6)). It has been found that a cellular ATP-binding cassette transporter (ABC) called ABCA1 mediates the first step of RCT. Mutations in ABCA1 cause Tangier disease (TD), a severe HDL deficiency syndrome characterized by accumulation of cholesterol in tissue macrophages and prevalent atherosclerosis. Studies of TD heterozygotes revealed that ABCA1 activity is a major determinant of plasma HDL levels and therefore predisposes for coronary vascular diseases such as atherosclerosis (6). Evidence from epidemiological studies suggests that the development of small, dense LDL (LDL subclass phenotype B) can also be genetically influenced (15/16). Other factors genetically linked to the changes in blood lipids include: liver x receptors (LXR's). LXR's (LXRalpha and LXRbeta) are nuclear receptor transcription factors that are activated by certain oxysterol derivatives of cholesterol. Millatt et al reported that LXR's play an important role in the response to excess cholesterol and by using an LXR agonist (Ghr3965) they were able to demonstrate a dramatic anti-atherosclerotic effect in mice (11). This can be taken as evidence of a genetic link of LXR genes to atherosclerosis.

Endothelial cell changes: endothelial dysfunction is characterised by reduced bioactivity of nitric oxide (NO). Channon et al reported an important role for both the NAD(P)H oxidases and endothelial NOS in the increased vascular superoxide production associated with endothelial dysfunction predisposing human vascular disease states (10).
Macrophage responses: During the process of atherosclerosis, the homeostatic mechanisms (which are genetically controlled) of a macrophage fail and uncontrolled cholesterol deposition is promoted by the scavenger functions of the macrophages (12).
Diabetes/Obesity: People with diabetes tend to be predisposed to atherosclerosis due to their accelerated synthesis of LDL's (3).

Protective factors:
There have been a lot less factors (genetically linked) identified that protect against the development of atherosclerosis. It is known however that pre-menopausal women are to a degree protected from developing the disease. Walters et al reports that oestrogen deficiency in postmenopausal women may contribute to endothelial dysfunction, together with other modifiable risk factors and that the absolute risk of coronary disease is greater for men than for pre-menopausal women (13). This suggests that oestrogen somehow protects women from atherosclerosis.

Most risk factors for atherosclerosis are associated with impaired endothelium-dependent vasodilatation due to reduced NO production. Folate/folic acid not only reduces plasma homocysteine levels but also enhances eNO synthesis and shows anti-inflammatory actions thereby also providing protection against the development of atherosclerosis (14). The LPL S447X cSNP has been reported to be associated with decreased blood pressure and plasma triacylglycerides and increased high-density lipoprotein cholesterol (all atherosclerosis risk factors) (17). Clee et al reported a reduced risk of coronary artery disease suggesting that this polymorphism is protective against atherosclerosis. Observations that apoE deficient mice develop spontaneous atherosclerosis, whereas transgenic mice expressing a defective apoE from the liver do not, suggesting that macrophage apoE secretion may indeed play a protective role in regard to atherosclerosis susceptibility (2).

Atherosclerosis is a multi factorial process that can start in utero, it progresses over decades and leads to cardiovascular complications such as heart attacks and strokes. This disease accounts for a large proportion of morbidity and mortality in the western world and is affected by both environmental and genetic risk factors. Understanding the complexity and functional relevance of these risk factors especially the genetic factors (predisposing to or protecting from) can improve the early detection, management and prevention of this disease.
For example, mutations in the ABCA1 gene lower HDL levels thereby predisposing the subject to atherosclerosis. Knowing how this mutation affects the development of atherosclerosis allows for possible gene/protein therapy methods to be investigated. It is also known that macrophage apoE secretion may play a protective role in regard to atherosclerosis susceptibility, therefore methods can now be investigated as to possibly inducing apo E synthesis/secretion to help protect patients with a high risk of developing the disease.

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