Proteomics of Cardiovascular Risk: The Multiethnic Study of Atherosclerosis

项目摘要 动脉粥样硬化性心血管疾病（ASCVD）和心力衰竭（HF）仍然是老年人死亡的主要原因。 尽管治疗方法有所改进，但首次ASCVD和HF事件的发生率仍然高得不可接受。 在预防和管理这些疾病方面取得进展需要更好地了解其新风险 因素和生物途径。蛋白质水平可以作为有效的，特异性的和可改变的生物标志物， ASCVD和HF风险，指导治疗并阐明因果途径。大规模蛋白质组技术已经 可在0.15 ml血浆中同时扫描4，993种不同的蛋白质， 适体作为结合试剂。该提案的首要目标是将大规模蛋白质组学应用于 无心血管疾病（CVD）的患者，以改善ASCVD和HF风险预测， 增加对这些疾病发展的生物学途径和机制的了解， 疾病我们将在MESA进行蛋白质组学研究，MESA是一个特征良好、种族多元化的队列， 2000年至2002年招募的6814名基线时无心血管疾病的人。从最初的15年到现在， 研究访视时，已累积> 800起心血管事件，为ASCVD和HF风险提供了机会 建模MESA的主要目标是研究"亚临床到临床CVD的进展， 冠状动脉钙化（CAC）作为ASCVD的亚临床指标，心脏MR（CMR）作为亚临床指标 测量HF。因此，除了ASCVD和HF临床结果的建模，我们将设计蛋白质组学方法， 亚临床ASCVD和HF发展及其转化为临床事件的风险评分。我们 将在三次研究访视中进行蛋白质组学研究，时间跨度为10年，以描述纵向蛋白质组学风险 轨迹，并创建"活的"可变风险分数。最后，在一个探索性的目标，我们将利用MESA的近 男女平等的代表性及其种族多样性，通过测试蛋白质组的任何异质性， 根据性别和种族，与ASCVD和HF相关的风险评分和生物学途径。模型 ASCVD和HF风险将在MESA内开发，然后在动脉粥样硬化风险中进行外部验证， 社区（ARIC）队列。总之，我们的目的是测定4，993种血浆蛋白的浓度， 6，043名MESA参与者参加了3次研究访问，时间跨度为10年，目的是：1）改善事故风险预测 ASCVD和HF结局以及早期亚临床疾病，2）告知ASCVD事件的生物学途径 和HF结果和亚临床疾病，3）告知生物学和倾向性的性别和种族差异， 发展ASCVD和HF，以及4）验证ARIC队列中的关键发现。

PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) remain the leading cause of mortality in the U.S. Despite improved therapies, the incidence of first ASCVD and HF events is still unacceptably high. Progress in preventing and managing these conditions will require a better understanding of their novel risk factors and biological pathways. Protein levels can serve as potent, specific, and modifiable biomarkers for ASCVD and HF risk, guide therapy and elucidate causal pathways. Large-scale proteomic technology has become available to scan 4,993 distinct proteins simultaneously in just 0.15 ml of plasma, using modified aptamers as binding reagents. The overarching goal of this proposal is to apply large-scale proteomics to patients who are free of cardiovascular disease (CVD) to improve incident ASCVD and HF risk prediction and increase understanding of the biological pathways and mechanisms underlying the development of these diseases. We will conduct the proteomic investigation in MESA, a well-characterized, racially diverse cohort of 6814 persons without CVD at baseline, recruited between 2000 and 2002. Now >15 years out from the initial study visit, >800 cardiovascular events have accumulated, providing an opportunity for ASCVD and HF risk modeling. MESA was conceived with the primary goal to study “progression of subclinical to clinical CVD, with coronary artery calcification (CAC) as a subclinical measure of ASCVD and cardiac MR (CMR) as a subclinical measure of HF. Thus, in addition to modeling of ASCVD and HF clinical outcomes, we will devise proteomic risk scores for the development of subclinical ASCVD and HF and for their conversion to clinical events. We will conduct proteomic studies at three study visits that span 10 years, to delineate longitudinal proteomic risk trajectories and create “live” mutable risk scores. Lastly, in an exploratory aim, we will leverage MESA’s near equal representation of men and women and its racial diversity by testing for any heterogeneity of proteomic risk scores and biological pathways associated with ASCVD and HF, according to sex and by race. Models for ASCVD and HF risk will be developed within MESA and then externally validated in the Atherosclerosis Risk in Communities (ARIC) cohort. In sum, our Aims are to assay the concentrations of 4,993 plasma proteins in 6,043 MESA participants at 3 study visits spanning 10 years to: 1) improve the risk prediction of incident ASCVD and HF outcomes and earlier subclinical disease, 2) inform the biological pathways of incident ASCVD and HF outcomes and subclinical disease, 3) inform sex and racial differences in the biology and propensity to develop ASCVD and HF, and 4) validate key findings in the ARIC cohort.