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、抵抗素、脂联素、肿瘤坏死因子α (tnf - α)和纤溶酶原激活物抑制剂1 （PAI-1）对炎症和血栓反应有深远的影响。肥胖导致的它们的失调可能通过增加动脉壁对动脉粥样硬化损伤的反应性来促进动脉粥样硬化。为了在人类中验证这一假设，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。为此，我们将在400例cad阳性病例和400例cad阴性的肥胖和糖尿病患者中研究18个脂肪因子或其受体的基因。在这两种情况下，脂肪因子对动脉粥样硬化的影响可能会变得特别明显。为了对这些基因座进行全面的分析，我们将结合多种方法，最大限度地筛选功能区域，同时促进发现目前未被识别的调控序列中的变异。我们的具体目标是：1。表征已知和新型脂肪因子基因的变异，以确定最能捕获这些位点变异的多态性。2. 在一个以医院为基础的大型人群中，研究这些变异或由它们定义的单倍型是否与CAD相关。3. 探讨基因多态性影响冠心病风险的生物学机制。识别影响冠心病风险的变异将指出特定的脂肪因子和下游效应物是肥胖与血管损伤相关的潜在机制。这一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，对CAD易感性的遗传标记的了解将使CAD高风险个体的识别成为可能，因此预防方案可以在生命早期专门针对这些受试者。

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.