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.
Proteins perform most biologic functions and are often the target of drug therapies. The primary goal of the project is to use proteomics to enhance our understanding of population biology and the etiology of chronic disease in older adults. Associations identified in the proposed project may identify novel targets for new therapies, new uses for existing drugs, and potential new safety concerns.
