Variability in Adipokine Genes and Atherosclerosis

描述（由申请人提供）：最近的证据表明，脂肪组织分泌的分子或脂肪因子是肥胖和心血管疾病之间的重要联系。脂肪因子，包括瘦素、脂联素、肿瘤坏死因子α（TNF-α）和纤溶酶原激活物抑制剂1（派-1），对炎症和血栓形成反应具有深远的影响。肥胖导致的它们的失调可能通过增加动脉壁对致动脉粥样硬化损伤的反应性而促进动脉粥样硬化。作为在人类中检验这一假设的一种方法，我们将研究影响这些分子表达或活性的遗传变异是否会影响冠状动脉疾病（CAD）的发展。我们将通过研究400例CAD阳性病例和400例CAD阴性对照肥胖和糖尿病患者的18种脂肪因子或其受体基因来做到这一点-这两种情况下脂肪因子对动脉粥样硬化的影响可能变得特别明显。为了对这些基因座进行全面分析，我们将使用多种方法的组合，这些方法将最大限度地提高筛选功能区域的能力，同时促进发现目前未识别的调控序列中的变体的贡献。我们的具体目标是：1.描述已知和新的脂肪因子基因的变异，以确定最能捕捉这些基因座变异的多态性。2.在大型医院人群中调查这些变异或由它们定义的单倍型是否与CAD相关。3.研究多态性影响CAD风险的生物学机制。对影响CAD风险的变异的鉴定将指出特定的脂肪因子和下游效应物是将肥胖与血管损伤联系起来的潜在机制。这些知识可能为开发药物或生活方式干预以预防超重或肥胖人群的动脉粥样硬化提供新的策略。此外，CAD易感性的遗传标记的知识将允许在CAD的高风险的个人识别，使预防方案可以专门针对这些主题在生命的早期。

DESCRIPTION (provided by applicant): 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.