Genetics of CRP in families with myocardial infarction

心肌梗死家族 CRP 遗传学

• 批准号: 6757284
• 负责人: ULRICH BROECKEL
• 金额: $ 37.09万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6757284
• 关键词: Hispanic Americans; acute phase protein; biomarker; cardiovascular disorder risk; caucasian American; clinical research; coronary disorder; genetic susceptibility; human subject; linkage mapping; myocardial infarction; quantitative trait loci; racial /ethnic difference; single nucleotide polymorphism

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.

描述（由申请人提供）：冠状动脉疾病（CAD）和心肌梗塞（MI）是西方世界的主要原因。 大量流行病学研究已经证明了各种危险因素的影响，例如动脉高血压、高胆固醇血症和糖尿病。 虽然这些危险因素部分受到遗传控制，但阳性家族史仍然是 CAD 的另一个独立预测因子，表明存在尚未确定的易感位点。 鉴于 CAD 给公共卫生带来的巨大负担，人们对确定其特定的遗传基础非常感兴趣。 随着深入的实验研究的继续，导致动脉粥样硬化的疾病过程中的炎症成分逐渐成为疾病过程中的一个关键方面。 最近的证据表明，C 反应蛋白 (CRP) 等全身炎症标志物可以预测冠状动脉事件高风险人群。 CRP 作为诊断标志物和治疗靶标而受到广泛关注，其血清水平在很大程度上由遗传因素决定。 作为该项目的总体目标，我们建议通过遗传连锁和关联研究，努力阐明 CRP 的遗传基础及其遗传影响以及与 CAD/MI 的关系。 在患有 MI 的家庭中，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，我们还确认了不同独立群体中 CRP 的连锁信号。 作为阐明 MI 炎症成分和 CRP 调节的遗传基础的一种手段，我们提出了对候选基因进行以基因功能为导向的评估，这些候选基因映射到上述 QTL。 因此，具体目标如下： 1.我们将在我们已确定的 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。 我们将鉴定选定候选基因中的序列变异。 2. 我们将评估这些变异对两个不同种族人群中 MI 和 CRP 的影响：我们的欧洲白种人家庭集和基于人口的西班牙裔家庭数据集。 我们将进一步评估 CRP 在我们的研究人群中作为心血管事件预测因子的作用。 由于我们拥有两个研究人群的临床随访数据，我们将在家庭分析框架内测试 CRP 在多大程度上导致心血管事件风险增加。