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着重要作用。系统地研究基因变异在多大程度上决定了动脉粥样硬化的风险和进展的工具直到现在才变得可行。本项目的总体目的是评估29个位点炎症通路基因的遗传变异在颈动脉粥样硬化性疾病（CAAD）的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起始和进展的基因。我们将评估常见位点单倍型的snp信息。评价信息多态性的选择是基于基因的进化史。我们将对CAAD患者进行为期3年的无创磁共振（MR）技术纵向随访的进展效应进行评估。风险将通过病例-对照比较来评估。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蛋白水平的干预表型。将评估遗传预测因子与传统心血管危险因素的独立性。

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.