miRNAs, Whole Diet, and Coronary Heart Disease

完整的饮食，即食物和饮料的结合，在预防和治疗糖尿病中是重要的 冠心病(CHD)。饮食摄入量是人类不可或缺的终生环境因素。 虽然基因-环境相互作用在CHD中起着关键作用，但目前还不完全清楚整个饮食是如何 调节基因表达，以及这种调节是否是整个饮食和CHD之间的机械性联系。 MicroRNAs(MiRs)在转录后调控基因表达。饮食模式已经习惯于 评估整个饮食。在我们的初步研究中，我们证明了MIR与健康的整体相关。 饮食模式、“改良地中海饮食(MMedDiet)模式”和前瞻性地与CHD相关。 因此，我们的总体目标是前瞻性地研究MIR和CHD的饮食调节，以便更好地 在大队列中了解饮食对基因表达的调节及其与冠心病的关系。我们的 初步数据显示，mMedDiet模式与以下井中的低CHD风险有前景相关- 社区动脉粥样硬化风险研究(ARIC)。同样，我们的 已发表的数据显示，mMedDiet模式可能与亚临床动脉粥样硬化程度较低相关。 在一个具有良好特征的多种族队列中，动脉粥样硬化的多种族研究(MESA)。因此，我们 建议在ARIC和MESA队列中嵌套的两阶段、单独匹配的病例对照研究(1：2)。 在年龄、性别、种族、场地中心、血浆采集日历日期和冷冻/解冻周期方面进行匹配，使用 风险集抽样，我们将包括412例冠心病事件病例和824例ARIC(阶段)的风险集匹配对照 1用于基于下一代测序的MIR措施)和2阶段，Replication─361例冠心病事件 以及来自MESA的722个风险集匹配对照。捕捉到整个饮食的复杂性和众多 食品(包括营养素、食品成分和物质，如 添加剂和防腐剂)，我们将使用多种健康饮食模式。系统MIR将在 使用ARIC中最先进的小RNA-SEQ的血浆，以及候选和筛选的MIR将被测量 在ARIC和MESA中使用qPCR。我们的目标是确定具有成本效益的：1)整个饮食是否代表 通过健康的饮食模式，可能与MIR相关；以及2)诊断前的MIR是否 可能与冠心病发病相关的因素与整体饮食有关。我们将确定与饮食相关的和与冠心病相关的 候选MIR和其他MIR的MIR。我们将进一步评估MIR在多大程度上解释了 饮食得分较高的参与者和饮食得分较低的参与者之间存在冠心病风险。来自我们的调查结果 研究将阐明MIR作为一种将整个饮食与CHD事件联系起来的新途径，并将为 利用miRs作为基因饮食调节的新生物标志物和作为评估新疗法的代用品 预防冠心病事件的方法和公共卫生战略。

The whole diet, the combination of foods and beverages, is important in the prevention and treatment of coronary heart disease (CHD). Dietary intake is a life-long environmental factor indispensable for humans. Although the gene-environment interaction is pivotal in CHD, it is not completely known how the whole diet regulates gene expression, and whether such regulation is a mechanistic link between the whole diet and CHD. MicroRNAs (miRs) regulate gene expression post-transcriptionally. Dietary patterns have been used to evaluate the whole diet. In our pilot studies, we demonstrated that miRs were associated with a healthy whole diet pattern, “modified Mediterranean diet (mMedDiet) pattern”, and were prospectively associated with CHD. Thus, our overall objective is to prospectively investigate dietary modulation of miRs and CHD for better understanding of dietary regulation of gene expression and its relation to CHD in the large cohort. Our preliminary data showed that a mMedDiet pattern was prospectively associated with low CHD risk in a well- characterized community cohort, the Atherosclerosis Risk in Communities Study (ARIC). Similarly, our published data showed that a mMedDiet pattern was prospectively related to lower subclinical atherosclerosis in a well-characterized, multi-ethnic cohort, the Multi-Ethnic Study of Atherosclerosis (MESA). Therefore, we propose a two-phase, individually matched case-control (1:2) study nested in both ARIC and MESA cohorts. Matching on age, sex, race, field center, calendar date for plasma collection, and freeze/thawing cycle, using risk-set sampling, we will include 412 incident CHD cases and 824 risk-set matched controls from ARIC (phase 1 for next-generation sequencing based miR measures) and for phase 2, replication ─ 361 incident CHD cases and 722 risk-set matched controls from MESA. To capture the complex nature of the whole diet and numerous synergies and antagonism among food items (including nutrients, food components, and substances such as additives and preservatives), we will use multiple healthy dietary patterns. Systemic miRs will be profiled in plasma using the state-of-the art small RNA-seq in ARIC, and candidate and screened miRs will be measured using qPCR in ARIC and MESA. We aim to determine cost-efficiently: 1) whether the whole diet represented by healthy dietary patterns, is prospectively associated with miRs; and 2) whether pre-diagnosis miRs that are prospectively related to incident CHD are associated with whole diet. We will identify diet-related and CHD-related miRs from candidate miRs and other miRs. We will further assess to what extent miRs explain the difference in CHD risk between participants with higher diet scores and those with lower diet scores. Findings from our study will shed light on miRs as a novel pathway linking whole diet to CHD event, and will provide insight into the use of miRs as novel biomarkers for dietary regulation of genes and as proxies to evaluate new therapeutic approaches and public health strategies to prevent CHD events.