Discovery, Replication, and Validation of Biomarkers of the DASH Diet and Hypertension

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ABSTRACT Preclinical and observational evidence supports a cardioprotective role of vitamin D. However, vitamin D supplementation in randomized controlled trials has failed to reduce cardiovascular events or cardiovascular mortality. Characterizing metabolites and proteins associated with vitamin D supplementation, assessing their associations with cardiovascular disease, and examining sources of heterogeneity may help to elucidate mechanisms underlying the epidemiological associations and yield insights into the discrepant null findings in clinical trials. While serum 25(OH)D is commonly measured to assess vitamin D status and its association with disease outcomes, it does not directly reflect biologically available vitamin D or its functions in the body. High-throughput technologies can identify thousands of metabolites and proteins in blood and urine, which may provide a more comprehensive understanding of vitamin D metabolism than serum 25(OH)D. We propose to investigate novel biomarkers of vitamin D supplementation in the Atherosclerosis Risk in Communities Study (ARIC) using untargeted metabolomic and proteomics, as well as examine prospective associations between vitamin D-related metabolites and proteins with cardiovascular outcomes. This cost-effective proposal leverages existing omics data in a richly phenotyped cohort of black and white older adults with validated cardiovascular outcomes. Untargeted metabolomics of both serum and urine, and untargeted plasma proteomics, have already been analyzed using specimens collected at ARIC visit 5. Our multi-omic approach maximizes opportunities for biomarker discovery, as well as exploration of how these biomarkers vary according to participant characteristics including sex, race, and body mass index. The study team is led by an R01-funded investigator with extensive experience analyzing metabolomics and proteomics of dietary exposures and chronic disease outcomes. The proposed research will advance knowledge of vitamin D metabolism and characterize pathways through which vitamin D supplementation may promote cardiovascular health.