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A Review and discussion of the evidence for a genetic link to Atherosclerosis
Introduction
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 (). It is believed to be a multifactorial process, which can in some cases start in utero (). 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.
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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), (). 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 (LXRs). LXRs (LXRalpha and LXRbeta) are nuclear receptor transcription factors that are activated by certain oxysterol derivatives of cholesterol. Millatt et al reported that LXRs play an important role in the response to excess cholesterol and by using an LXR agonist (Ghr65) 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 (1).
Diabetes/Obesity People with diabetes tend to be predisposed to atherosclerosis due to their accelerated synthesis of LDLs ().
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 (1). 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 ().
Conclusion
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.
References
1. University of Otago Genetics 1 Laboratory manual for 00.
. CRISP - project title Bone marrow transplantation and atherosclerosis
URL crisp.cit.nih.gov/
. Szitanyi, P; Janda, J; Polende, R; Intrauterine undernutrition and programming as a new risk of cardiovascular disease in later life. Physiol. Res. 5 8 - 5, 00
4. Libby, P; Atherosclerosis a new view Scientific American pp. - 7 may 00
5. The Donald W. Reynolds Cardiovascular clinical research centre
URL www-med.stanford.edu/reynolds/summary.htm
6. Oram, JF; Lawn, RM; ABCA1 The gatekeeper for eliminating excess cholesterol. Lipid Res. 001 Aug; 4(8) 117 -
7. Zhang, Z; Yamashita, S; Hirano, K; Nakagawa-Toyama, Y; Matsuyama, A; Nishida, M; Sakai, N; Fukasawa, M; Arai, H; Miyagawa, J; Matsuzawa, Y; Expression of cholesterol ester transfer protein in human atherosclerotic lesions and its implications in reverse cholesterol transport. Atherosclerosis 001 Nov; 15(1 ) 67 - 75
8. Berthier, MT; Houde, A; Bergenon, J; Prudacte;homme, D; Despres, JP; Vohl, MC; Effect of the factor V11 R5Q missense mutation on plasma apolipoprotein B levels impact of visceral obesity. J. Hum Genet. 00 Jul; 48(7) 67 - 7
. Cottrell, DA; Marshall, BJ; Falko, JM; Therapeutic approaches to dyslipidemia in diabetes mellitus and metabolic syndrome. Curr. opin Cardiol. 00 Jul; 18(4) 01-8
10. Channon, KM; Guzik, TJ; Mechanisms of superoxide production in human blood vessels relationship to endothelial dysfunction, clinical and genetic risk factors. J. Physiol. Pharmacol. 00 Dec; 5(4 pt 1) 515 - 4
11. Millatt, LJ; Bocher, V; Fruchart, JC; Staels, B; Liver x receptors and the control of cholesterol homeostasis potential therapeutic targets for the treatment of atherosclerosis. Biochem Biophys Acta. 00 Mar 17; 161() 107 - 18
1. Rainio, S; Ikomen, E; Macrophage cholesterol transport a critical player in foam cell formation. Ann. Med 00; 5() 146 - 55
1. Walters, J; Skene, D; Hampton, SM; Ferns, GA; Biological rhythms, endothelial health and cardiovascular disease. Med Sci Monit. 00 Jan; (1) RA 1 - 8
14. Das, UN; Folic acid says NO to vascular diseases. Nutrition 00 Jul - Aug;
1(7 - 8) 686 -
15. Austin, MA; Genetic epidemiology of dyslipidemia and atherosclerosis. Ann Med. 16 Oct; 8(5) 45 - 6
16. Superko, HR; Did grandma give you heart disease? The new battle against coronary artery disease. Am J Cardiol. 18 Nov 5; 8(A) 4Q - 46Q
17. Clee, SM; Loubser, O; Collins, J; Kastelein, JJP; Hayden, MR; The LPL S447X cSNP is associated with decreased blood pressure and plasma triacylglycerides, and reduced risk of coronary arter ease. Clinical genetics 001 Oct; 60(4)Please note that this sample paper on Atherosclerosis is for your review only. In order to eliminate any of the plagiarism issues, it is highly recommended that you do not use it for you own writing purposes. In case you experience difficulties with writing a well structured and accurately composed paper on Atherosclerosis, we are here to assist you. Your cheap custom research papers on Atherosclerosis will be written from scratch, so you do not have to worry about its originality.
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