Plasma proteomics in CHS and population biology

在心血管疾病和衰老的研究中，各种组学数据的出现， 改变了人口科学例如，在过去的十年中，全基因组关联研究（GWAS） 已经确定并复制了数千种与健康和疾病有关的遗传关联。他们的 主要贡献是提高了对各种健康疾病病因学的认识， 人类种群生物学。这些发现的努力可以迅速导致新的疗法，如 PCSK9抑制剂同样，蛋白质组学可以促进我们对生物学的理解。蛋白质执行 大多数生物学功能，它们往往不仅是药物治疗的目标，而且是关键的生物标志物， 临床医学技术的最新进展已经改进了多重蛋白质测定，并且使得 大规模的人类研究是容易处理的。 本课题拟对3200例心血管健康研究中的1310种血浆蛋白进行检测 (CHS)参与者使用基于适体的方法，该方法对低丰度蛋白质具有高灵敏度 以及对于大量样品的高通量。一项老年人队列研究，CHS目前提供了 积极支持八个表型特异性工作组（WG），包括中心分析。每个CHS 工作组由一名或两名高级研究人员领导，包括10至20名初级或中级科学家。与 在基因组学和资助工作组模式的经验，CHS是组织良好，以利用新的大型， 规模表型分析技术，如蛋白质组学，以促进人类健康和疾病的知识。 该项目的目标是利用蛋白质组学来提高我们对疾病病因学的理解， 预防老年人。主要假设包括评估基线水平和基线水平之间的关联。 前瞻性队列中的循环蛋白水平和各种健康结局的发生率 在CHS中分析。计划是立即向八个CHS工作组发布蛋白质测定结果， 他们的115名研究人员，为工作组提供中央分析支持，提供基于质谱的 验证选定的蛋白质，并利用在心脏病研究中复制的机会 和杰克逊心脏研究。多种形式的遗传数据，包括全基因组序列数据，也是 可用于验证蛋白质的身份并确定其遗传决定因素。此外，孟德尔 随机化分析将用于检查以下因素之间因果关系的支持性证据： 蛋白质水平和健康结果。对于关键蛋白质，将开发新的ELISA检测方法， 临床研究这一建议的意义在于， 老年人队列，严格验证的蛋白质组学技术，可用的遗传数据，WG 结构，分析的中心支持，测定验证工作，复制计划，生产 CHS WG成员和数据共享计划。

In studies of cardiovascular disease and aging, the emergence of various types of omics data has transformed population science. In the last decade, for instance, genome-wide association studies (GWAS) have identified and replicated thousands of genetic associations with measures of health and disease. Their primary contribution has been an improvement in the understanding of the etiology of a variety of health conditions—human population biology. These discovery efforts can lead rapidly to new therapies such as the PCSK9 inhibitors. Likewise, proteomics can advance our understanding of biology. Proteins perform most biological functions, and they are often not only the target of drug therapies, but also key biomarkers in clinical medicine. Recent advances in technology have improved multiplexed protein assays and made large scale studies in humans tractable. In the proposed project, we plan to assay 1310 plasma proteins in 3200 Cardiovascular Health Study (CHS) participants with an aptamer-based method, one that has high sensitivity for low-abundance proteins and high throughput for a large number of samples. A cohort study of older adults, CHS currently provides active support, including central analysis, for eight phenotype-specific working groups (WGs). Each CHS WG is led by one or two senior investigators and includes 10 to 20 junior or mid-career scientists. With experience in genomics and a funded WG model, CHS is well-organized to take advantage of novel large- scale phenotyping techniques such as proteomics to advance knowledge of human health and disease. The goal of the project is to use proteomics to improve our understanding of disease etiology and prevention in older adults. The primary hypotheses involve an evaluation of associations between baseline levels of circulating proteins and the incidence of a variety of health outcomes in prospective cohort analyses in CHS. The plans are to release the protein-assay results immediately to the eight CHS WGs and their 115 investigators, to provide central analytic support to the WGs, to offer mass-spectrometry-based validation of selected proteins, and to leverage opportunities for replication in the Framingham Heart Study and Jackson Heart Study. Multiple forms of genetic data, including whole-genome sequence data, are also available to verify the identity of proteins and to establish their genetic determinants. In addition, Mendelian randomization analyses will be used to examine supportive evidence for causal associations between protein levels and health outcomes. For key proteins, new ELISA assays will be developed for additional clinical research. The significance of this proposal lies in the combined strengths of the well-phenotyped cohort of older adults, the rigorously validated proteomic technique, the available genetic data, the WG structure, the central support for analysis, the assay validation efforts, the replication plans, the productive CHS WG members, and the data-sharing plans.