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，在过去的十年里，全基因组关联研究(GWAS) 已经确定并复制了数以千计的基因与健康和疾病的衡量标准。他们的 主要的贡献是对各种健康疾病的病因的理解有所改善 条件--人类种群生物学。这些发现努力可以迅速带来新的治疗方法，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。蛋白质发挥作用 大多数生物功能，而且它们通常不仅是药物治疗的靶点，而且也是 临床医学。最近在技术上的进步改进了多重蛋白质分析，并使 在人类身上进行大规模研究是容易处理的。 在拟议的项目中，我们计划在3200心血管健康研究中检测1310种血浆蛋白 (CHS)使用基于适体的方法的参与者，该方法对低丰度蛋白具有高敏感性 以及大量样品的高吞吐量。一项针对老年人的队列研究，CHS目前提供了 积极支持八个具体表型工作组，包括中央分析。每个CHS 工作组由一到两名高级调查人员领导，包括10到20名初级或职业生涯中期的科学家。使用 在基因组学方面的经验和一个资助的WG模式，CHS组织得很好，以利用新的大型 推广蛋白质组学等表型技术，以促进对人类健康和疾病的了解。 该项目的目标是使用蛋白质组学来提高我们对疾病病因学和 老年人的预防。主要假设包括对基线之间的关联进行评估 前瞻性队列中循环蛋白水平与各种健康结局的发生率 CHS中的分析。计划是立即向8个CHS WGS发布蛋白质分析结果，并 他们的115名调查人员，为WGS提供中央分析支持，提供基于质谱学的 验证选定的蛋白质，并在Framingham心脏研究中利用复制机会 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 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 随机化分析将被用来检验支持证据的因果关系 蛋白质水平和健康结果。对于关键蛋白质，将开发新的ELISA法来检测其他 临床研究。这一建议的意义在于结合了表型良好的 老年人队列，经过严格验证的蛋白质组技术，可用的遗传数据，工作组 结构、分析的中央支持、化验验证工作、复制计划、生产 CHS工作组成员，以及数据共享计划。

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.