Mediterranean diet, Metabolites, and Cardiovascular Disease

摘要 代谢组学技术有望更好地了解饮食在心血管疾病（CVD）中的作用 流行病学和预防。特别是，结合尿液和血液的多流体多代谢物方法， 血浆代谢组学可能会提高营养生物标志物的准确性和精确性， 在精确营养研究中开发新的膳食评估工具的潜力。这种竞争性的更新 目的是检查随机地中海饮食（MedDiet）干预对泌尿系统的影响。 代谢物水平，并评估饮食生物标志物对未来CVD风险的预测能力， PREDIMED试验。我们将通过病例队列设计评估与CVD相关的尿代谢组学， 包括从所有PREDIMED参与者（10%，n=779）中随机抽样的代表性子队列，以及 新发CVD病例（包括心肌梗死（MI）、卒中、心力衰竭和心血管死亡） 截至2017年12月（n=529）。本研究的具体目的是：（1）鉴定特定的尿代谢产物 和多代谢物特征的MedDiet模式及其主要食物成分;（2）检查 随机饮食干预对尿多代谢物特征变化的影响 从基线到第1年（干预后）的MedDiet模式及其主要食物成分;（3）调查 MedDiet模式和MedDiet模式的尿多代谢物特征的基线和1年变化 个别食物与随后的心血管疾病风险有关;（4）发展多流体（尿液和 血浆）多代谢物特征，其稳健地预测CVD的风险，并评估 该特征介导了饮食干预对复合CVD结果的影响。作为子目标，我们 将比较MedDiet模式的血浆和尿液代谢物对CVD风险的预测作用。这 持续赠款始于2013年，并于2017年续签。到目前为止，已发表36篇论文或 已提交（包括本赠款周期内的20篇论文）。PREDIMED代谢组学数据已被 用作在几个美国队列中复制CVD结果的代谢组学分析的资源。这 竞争性的更新申请将把我们长期以来对MedDiet和CVD的研究扩展到多流体多 在一项大型随机干预试验中进行代谢物分析。该项目利用了 PREDIMED试验，一个多学科和高效的团队，尖端的代谢组学技术， 高维数据分析确定的饮食生物标志物将提高质量和严谨性， 营养研究，加强制定膳食建议和营养的证据基础 施政纲要而拟议的工作将促进2020-2030年概述的精准营养研究议程 NIH营养研究战略计划。

ABSTRACT Metabolomics technique holds promise for better understanding the role of diet in cardiovascular disease (CVD) epidemiology and prevention. In particular, a multi-fluid multi-metabolite approach combining urinary and plasma metabolomics will likely enhance the accuracy and precision of nutritional biomarkers, with strong potential to develop novel tools for dietary assessment in precision nutrition research. This competing renewal is aimed to examine the effects of the randomized Mediterranean diet (MedDiet) interventions on urinary metabolite levels and to assess dietary biomarkers' predictive ability for future CVD risk in the landmark PREDIMED trial. We will assess urinary metabolomics in relation to CVD through a case-cohort design, including a representative subcohort randomly sampled from all PREDIMED participants (10%, n=779), and incident CVD cases (including myocardial infarction (MI), stroke, heart failure, and cardiovascular deaths) through December 2017 (n=529). The proposed Specific Aims are: (1) To identify specific urinary metabolites and multi-metabolite signatures of the MedDiet pattern and its main food components; (2) To examine the effects of the randomized dietary interventions on changes in the urinary multi-metabolite signatures of the MedDiet pattern and its major food components from baseline to year 1 (post intervention); (3) To investigate whether baseline and 1-year changes in urinary multi-metabolite signatures of the MedDiet pattern and of individual foods are associated with subsequent risk of CVD; and (4) To develop a multi-fluid (urine and plasma) multi-metabolite signature that robustly predicts risk of CVD and assess whether 1-year changes in the signature mediate the effects of the dietary interventions on the composite CVD outcome. As a sub-aim, we will compare the predictive roles of plasma and urinary metabolites of the MedDiet pattern on CVD risk. This ongoing grant started in 2013 and was renewed in 2017. To date, 36 papers have been published or submitted (including 20 papers in the current grant cycle). The PREDIMED metabolomics data have been used as a resource for replicating metabolomics analyses of CVD outcomes in several US cohorts. This competing renewal application will extend our long-standing research on MedDiet and CVD to multi-fluid multi- metabolite profiling in a large randomized intervention trial. This project leverages numerous strengths of the PREDIMED trial, a multi-disciplinary and highly productive team, cutting-edge metabolomics technologies, and high-dimensional data analytics. The identified dietary biomarkers will enhance the quality and rigor of nutrition research and strengthen the evidence base for developing dietary recommendations and nutrition policies. The proposed work will facilitate the precision nutrition research agenda outlined in the 2020-2030 Strategic Plan for NIH Nutrition Research.