Proteomics of Cardiovascular Risk: The Multiethnic Study of Atherosclerosis

项目总结 动脉粥样硬化性心血管疾病(ASCVD)和心力衰竭(HF)仍然是#年死亡的主要原因。 尽管美国的治疗方法有所改进，但首次ASCVD和心衰事件的发生率仍然高得令人无法接受。 在预防和管理这些疾病方面的进展将需要更好地了解它们的新风险 因素和生物途径。蛋白质水平可以作为有效的、特异的和可修改的生物标志物 ASCVD和心力衰竭的风险，指导治疗和阐明病因路径。大规模蛋白质组学技术已经 仅在0.15毫升的血浆中就可以同时扫描4993种不同的蛋白质，使用改进的 适配子作为结合试剂。这项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)的患者改善ASCVD和心力衰竭风险预测和 加深对这些疾病发生的生物学途径和机制的了解 疾病。我们将在梅萨进行蛋白质组学研究，梅萨是一个特征良好、种族多样的 在2000年至2002年期间招募的基线上没有心血管疾病的6814人。现在&gt；已经从最初的 研究访问，累积了800个心血管事件，为ASCVD和心力衰竭风险提供了机会 模特儿。MESA的构思的主要目标是研究“亚临床到临床CVD的进展， 冠状动脉钙化(CAC)是ASCVD的亚临床指标，心脏MR(CMR)是亚临床指标 高频量度。因此，除了对ASCVD和HF的临床结果进行建模外，我们还将设计蛋白质组学 亚临床ASCVD和心力衰竭的发展及其转化为临床事件的风险评分。我们 将在为期10年的三次研究访问中进行蛋白质组研究，以描绘纵向蛋白质组风险 轨迹，并创建“实时”可变的风险分数。最后，作为一个探索性的目标，我们将利用梅萨的NEAR 通过检测蛋白质组的任何异质性来实现男女平等代表及其种族多样性 根据性别和种族，与ASCVD和HF相关的风险分数和生物学途径。型号： ASCVD和HF风险将在MESA内发展，然后在动脉粥样硬化风险中进行外部验证 社区(ARIC)队列。总而言之，我们的目标是检测4993种血浆蛋白的浓度 参加为期10年的3次研究访问的6,043名MESA参与者：1)改进事件风险预测 ASCVD和HF的转归和早期亚临床疾病，2)告知ASCVD发生的生物途径 和心力衰竭的结局和亚临床疾病，3)告知性别和种族的生物学差异和倾向 开发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.