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

摘要 临床前和观察证据支持维生素D的心脏保护作用。 随机对照试验中补充维生素D未能减少心血管事件 或心血管疾病死亡率。与维生素D相关的代谢物和蛋白质的特征 补充，评估它们与心血管疾病的关系，并检查来源 异质性可能有助于阐明流行病学关联的潜在机制和 获得对临床试验中不一致的无效发现的洞察。而血清25(OH)D通常是 用来评估维生素D状况及其与疾病结局的关系，并不直接 反映生物可利用的维生素D或其在体内的功能。高吞吐量技术可以 鉴定血液和尿液中数以千计的代谢物和蛋白质，这可能提供更多 比起血清25(OH)D，对维生素D代谢的全面了解。我们建议 研究补充维生素D的新生物标志物在动脉粥样硬化风险中的作用 使用非靶向代谢组和蛋白质组学的社区研究(ARIC)，以及检查 维生素D相关代谢物和蛋白质与心血管疾病的前瞻性关联 结果。这一具有成本效益的建议利用了现有的组学数据，这些数据具有丰富的表型 黑人和白人老年人的心血管结果得到证实。非靶向代谢组学 血清和尿液，以及非靶向血浆蛋白质组学，都已经用 在ARIC访问上收集的标本5.我们的多组学方法最大限度地增加了生物标记的机会 发现，以及探索这些生物标志物如何根据参与者的特征而变化 包括性别、种族和体重指数。研究小组由一名R01资助的调查员领导， 分析饮食暴露和慢性疾病的代谢组学和蛋白质组学的丰富经验 疾病后果。这项拟议的研究将促进对维生素D新陈代谢和 描述补充维生素D可促进心血管健康的途径。

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.