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J Thromb Haemost. 2003 Jul;1(7):1381-90.

The genetics of atherothrombotic disorders: a clinician's view.

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Academic Unit of Molecular Vascular Medicine, University of Leeds School of Medicine, Leeds, UK.


The development of coronary artery disease is dependent on the interaction of multiple biochemical pathways that lead to the development of plaque in the arterial wall and ultimately plaque instability, plaque rupture and thrombosis. The latter stages lead to vascular obstruction, tissue death and the final phenotype of myocardial infarction. Hemostasis gene association studies of atherothrombotic disorders have been unrewarding, with largely underpowered studies reporting inconsistent results. Clinical studies such as the Multiple Risk Factor Intervention Trial clearly indicate that clustering of classical risk increases the likelihood of myocardial infarction, and the addition of diabetes mellitus to the risk profile exponentially increases the risk of a vascular event. The development of insulin resistance is considered to be a pivotal event in vascular risk with associated clustering of dysglycemia, hyperinsulinemia, systolic hypertension, raised triglyceride and low high-density lipoprotein cholesterol. Additionally, elevated levels of plasminogen activator inhibitor-1, factor (F)VII, FXII, fibrinogen and tissue plasminogen activator occur with insulin resistance to create an atherothrombotic risk cluster. Heritability studies of insulin resistance and the vascular risk profile demonstrate genetic pleitropy between diabetes and vascular risk, which indicate that common genes have an important role. Increasingly, it is felt that inflammation underpins both diabetes and cardiovascular disease and that the expression of the final phenotype(s) may depend on complex gene-environment interactions with regulatory genes, including those for nuclear transcription factors and RNA-binding proteins. The complexity of coronary artery disease and the risk factor interactions make it unlikely that genetic epidemiology will identify genes involved in these processes without a better understanding of environmental influences.

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