Genetics of CRP in families with myocardial infarction

描述(申请人提供)：冠状动脉疾病(CAD)和心肌梗死(MI)是西方世界主要的死亡原因。大量的流行病学研究已经证明了各种危险因素的影响，如动脉高血压、高胆固醇血症和糖尿病。虽然这些危险因素在一定程度上受基因控制，但阳性家族史仍然是冠心病的另一个独立预测因素，这表明存在尚未确定的易感基因。鉴于冠心病对公众健康造成的巨大负担，人们对确定其特定的遗传基础非常感兴趣。随着密集的实验研究的继续，导致动脉粥样硬化的疾病过程中的炎性成分逐渐成为疾病过程中的一个关键因素。最近的证据表明，C-反应蛋白(CRP)等系统炎症标志物可以预测冠状动脉事件的高危人群。C反应蛋白作为一种诊断标记物和治疗靶点备受关注，血清水平在很大程度上由遗传因素决定。作为这一项目的总体目标，我们建议通过遗传连锁和关联研究，努力阐明C反应蛋白的遗传基础及其对冠心病/心肌梗死的遗传影响和关系。在心肌梗死家系中，我们已经确定了心肌梗死的易感基因以及影响CRP水平的基因。此外，我们已经确认了CRP在不同的独立人群中的连锁信号。为了阐明心肌梗死炎症成分的遗传基础和C反应蛋白的调控，我们提出了一种面向基因功能的候选基因评估方法，这些基因定位于上述QTL。因此，我们的具体目标如下：1.我们将在已确定的MI和CRP区域内寻找与炎症和炎症过程功能相关的位置候选基因。我们将在选定的候选基因中识别序列变异。2.我们将评估这些变异在两个不同种族人群中对MI和CRP的影响：我们的欧洲高加索家族数据集和基于人群的西班牙裔家庭数据集。我们将进一步评估在我们的研究人群中，CRP作为心血管事件预测因子的作用。由于我们有两个研究人群的临床随访数据，我们将在我们的家庭分析框架内测试CRP对心血管事件风险增加的贡献程度。

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) and myocardial infarction (MI) are the leading causes of death in the Western world. Numerous epidemiological studies have demonstrated the impact of various risk factors, such as arterial hypertension, hypercholesterolemia and diabetes mellitus. While these risk factors are partly under genetic control, a positive family history remains an additional independent predictor of CAD, suggesting the presence of as yet unidentified susceptibility loci. Given the enormous public health burden of CAD, there is significant interest in identifying its specific genetic foundations. As intensive experimental investigations continue, the inflammatory component of the disease process leading to atherosclerosis evolves as a key aspect in the disease process. Recent evidence demonstrates that systemic markers of inflammation such as C-reactive Protein (CRP) can predict those at high risk of coronary events. CRP emerges with much attention as both a diagnostic marker and therapeutic target with serum levels determined to a significant extent by genetic factors. As the overall objective of this project, we propose to work towards clarifying the genetic basis of CRP and it's genetic influence and relation to CAD/MI through the use of genetic linkage and association studies. In families with MI we have identified a susceptibility locus for MI as well as loci influencing CRP levels. In addition, we have a confirmation of the linkage signals for CRP in a different, independent population. As a mean to elucidate the genetic basis of the inflammatory component of MI and the regulation of CRP, we propose a gene function-oriented evaluation of candidate genes, which map to the above mentioned QTLs. Therefore the specific aims are as follows, 1. We will identify positional candidate genes within regions we have identified for MI and CRP which are functionally related to inflammation and inflammatory processes. We will identify sequence variation in selected candidate genes. 2. We will evaluate the effect of these variants with regard to MI and CRP in two different ethnic populations: our family set of European Caucasians and a population-based, Hispanic family dataset. We will further evaluate the role of CRP as a predictor of cardiovascular events in our study populations. As we have clinical follow up data available on both of our study populations, we will test to what extent CRP contributes to an increased risk for cardiovascular events in the framework of our family analysis.