Recent evidence points to molecules secreted by the adipose tissue, or adipokines, as an important link between obesity and cardiovascular disorders. Adipokines, including leptin, resistin, adiponectin, tumor necrosis factors alpha (TNF-alpha), and plasminogen-activator inhibitor 1 (PAI-1) have profound effects on inflammatory and thrombotic responses. Their dysregulation as a consequence of obesity may promote atherosclerosis by increasing arterial wall's reactivity to atherogenic insults. As a way to test this hypothesis in humans, we will investigate whether genetic variants affecting these molecules' expression or activity influence the development of coronary artery disease (CAD). We will do so by studying 18 genes for adipokines or their receptors in 400 CAD-positive cases and 400 CAD-negative controls with obesity and diabetes - two conditions in which adipokines' effects on atherosclerosis may become especially evident. To provide a comprehensive analysis of these loci, we will use a combination of approaches that will maximize the power to screen functional regions, while fostering discovery of contributions from variants within currently unrecognized regulatory sequences.
Our specific aims are: 1. To characterize variation in known and novel adipokine genes in order to identify polymorphisms that best capture variability at these loci. 2. To investigate whether these variants, or haplotypes defined by them, are associated with CAD in a large hospital-based population. 3. To investigate the biological mechanisms through which polymorphisms may affect CAD risk. Identification of variants affecting CAD risk will point to specific adipokine(s) and downstream effectors as potential mechanisms linking obesity to vascular damage. This knowledge might suggest novel strategies for developing pharmacological or lifestyle intervention for preventing atherosclerosis in overweight or obese people. Furthermore, knowledge of genetic markers of susceptibility to CAD would allow the identification of individuals at high risk of CAD, so that preventive programs could be specifically targeted at these subjects early in life.
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