Inflammatory Genomics in Human Carotid Artery Disease

描述(申请人提供)：动脉粥样硬化性血管疾病是发病率和死亡率的主要来源。炎症在动脉粥样硬化中起着重要作用。系统地研究遗传变异决定动脉粥样硬化风险和进展的程度的工具直到现在才变得可用。本项目的总体目标是评估29个座位上炎症途径基因的遗传变异在颈动脉粥样硬化病(CAAD)风险和进展中的作用。待评估的基因包括那些可能参与斑块启动和进展的基因。我们将评估SNPs对常见基因座单倍型的信息性。选择信息丰富的多态进行评估是基于基因的进化史。我们将评估经过3年无创磁共振(MR)技术纵向追踪的CAAD受试者的进展效果。风险将通过病例对照比较进行评估。除了评估遗传多态之外，我们还将评估纤维蛋白原、C反应蛋白、血清淀粉样蛋白A和白细胞介素6的蛋白水平的介入性表型。将评估遗传预测因子与传统心血管危险因素的独立性。 主要的具体目标是：目的1.对550例CAAD患者(275例CAAD患者，275例CAAD狭窄程度为15-49%，275例CAAD狭窄程度为50-79%)进行为期3年的管腔狭窄百分比的磁共振成像随访，以评估炎症遗传效应和蛋白水平在CAAD进展中的作用；目的2.确定炎症基因或蛋白水平的变化是否可以预测810例与810例对照状态，基线时335例患者15-49%，275例50-75%，200例&GT；80%颈动脉狭窄。年龄(血管疾病的发病病例，对照的当前年龄)--性别、种族和医院匹配的对照在颈动脉双功超声上将有不到15%的狭窄。与疾病有牵连的基因最终可能会允许有针对性的治疗。

DESCRIPTION (provided by applicant): Atherosclerotic vascular disease is a major source of morbidity and mortality. Inflammation plays an important role in atherosclerosis. The tools to systematically study the extent to which genetic variation determines risk of and progression of atherosclerosis are only now becoming available. The general aim of this project is to evaluate the role of genetic variation in inflammatory pathway genes at 29 loci on the risk and progression of carotid artery atherosclerotic disease (CAAD). Genes to be evaluated include those potentially involved in plaque initiation and progression. We will evaluate SNPs informative for the common locus haplotypes. Choice of informative polymorphisms for evaluation is based on the genes' evolutionary history. We will evaluate progression effects in subjects with CAAD followed longitudinally by noninvasive magnetic resonance (MR) techniques over 3 years. Risk will be evaluated by case-control comparisons. In additions to evaluating genetic polymorphisms, we will evaluate the intervening phenotypes of protein level for fibrinogen, C-reactive protein, serum amyloid A, and interleukin-6. Independence of genetic predictors from traditional cardiovascular risk factors will be evaluated. The major specific aims are: Aim 1. Test for inflammatory genetic effects and protein level in CAAD progression in 550 subjects with CAAD (275 with 15-49% and 275 with 50-79% baseline CAAD stenosis) evaluated by 3-year magnetic resonance image follow-up of percent lumen stenosis; Aim 2. Determine whether the variation in the inflammatory genes or protein levels predicts 810 case vs. 810 control status with a case distribution of 335 subject with 15-49%, 275 with 50-75% and 200 with >80% carotid artery stenosis at baseline. Age (onset of vascular disease for cases, current age for controls)-, sex-, race-, and hospital-matched controls will have less than 15% stenosis on carotid duplex ultrasound. Genes that are implicated in disease may eventually allow targeted therapy.