Inflammatory Genomics in Human Carotid Artery Disease

描述（由申请人提供）：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现在才变得可用。本项目的总体目标是评估29个位点的炎症途径基因的遗传变异对颈动脉粥样硬化疾病（CAAD）风险和进展的作用。待评价的基因包括那些可能参与斑块起始和进展的基因。我们将评估SNP信息的共同位点单倍型。用于评估的信息多态性的选择是基于基因的进化历史。我们将在CAAD受试者中评估3年以上无创磁共振（MR）技术纵向随访的进展效应。将通过病例对照比较评价风险。除了评估遗传多态性外，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的蛋白质水平的干预表型。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：目标1。在550例CAAD受试者（275例基线CAAD狭窄率为15-49%，275例基线CAAD狭窄率为50-79%）中检测CAAD进展中的炎症遗传效应和蛋白质水平，通过3年磁共振成像随访管腔狭窄百分比进行评价;目的2。确定炎症基因或蛋白质水平的变化是否预测810例病例与810例对照状态，其中病例分布为335例受试者具有15- 49%，275例具有50-75%，200例具有>80%的基线颈动脉狭窄。年龄（病例为血管疾病发作，对照组为当前年龄）、性别、种族和医院匹配的对照组在颈动脉多普勒超声上的狭窄小于15%。与疾病有关的基因最终可能允许靶向治疗。

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.