Genetics of CRP in families with myocardial infarction

描述（由申请人提供）：冠状动脉疾病（CAD）和心肌梗死（MI）是西方世界的主要死亡原因。 许多流行病学研究已经证明了各种风险因素的影响，如动脉高血压、高胆固醇血症和糖尿病。 虽然这些危险因素部分受遗传控制，但阳性家族史仍然是CAD的另一个独立预测因素，表明存在尚未确定的易感基因座。 鉴于CAD的巨大公共卫生负担，确定其特定的遗传基础具有重大意义。 随着深入的实验研究的继续，导致动脉粥样硬化的疾病过程的炎症成分演变为疾病过程中的一个关键方面。 最近的证据表明，炎症的全身标志物，如C反应蛋白（CRP）可以预测冠状动脉事件的高风险。 CRP作为诊断标志物和治疗靶点受到了广泛关注，其血清水平在很大程度上由遗传因素决定。 作为本项目的总体目标，我们建议通过使用遗传连锁和关联研究，努力澄清CRP的遗传基础及其与CAD/MI的遗传影响和关系。 在MI家族中，我们已经确定了MI的易感位点以及影响CRP水平的位点。 此外，我们在不同的独立人群中确认了CRP的连锁信号。 作为阐明MI的炎症组分和CRP调节的遗传基础的手段，我们提出了定位于上述QTL的候选基因的基因功能导向评价。 因此，具体目标如下：1。 我们将在我们已经确定的MI和CRP区域内确定位置候选基因，这些基因在功能上与炎症和炎症过程相关。 我们将在选定的候选基因中鉴定序列变异。 2. 我们将在两个不同的种族人群中评估这些变异对MI和CRP的影响：我们的欧洲高加索人家庭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CRP作为我们研究人群中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，我们将在我们的家族分析框架内测试CRP在多大程度上导致心血管事件风险增加。

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.