miRNAs, Whole Diet, and Coronary Heart Disease

整个饮食，食物和饮料的组合，在预防和治疗 冠心病（CHD）。膳食摄入是人类终生不可缺少的环境因素。 尽管基因-环境相互作用在CHD中是关键的，但尚不完全清楚整个饮食如何影响CHD。 调节基因表达，以及这种调节是否是整个饮食和CHD之间的机械联系。 microRNA（miRs）在转录后调节基因表达。饮食模式已经被用来 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”，并与CHD前瞻性相关。 因此，我们的总体目标是前瞻性地研究miR和CHD的饮食调节， 了解基因表达的饮食调节及其与大队列中CHD的关系。我们 初步数据显示，在健康人群中，mMedDiet模式与CHD风险低相关， 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模式与亚临床动脉粥样硬化程度较低具有前瞻性相关性 在一个特征鲜明的多种族队列中，多种族动脉粥样硬化研究（梅萨）。所以我们 建议在ARIC和梅萨队列中进行一项两阶段、个体匹配的病例对照（1：2）研究。 年龄、性别、人种、田间中心、血浆采集日历日期和冻融循环匹配，使用 风险集抽样，我们将纳入412例新发CHD病例和824例来自ARIC（第 1用于基于下一代测序的miR测量）和2期，复制-361例CHD病例 和来自梅萨的722个风险集匹配对照。为了捕捉整个饮食的复杂性和众多的 食物项目之间的协同作用和拮抗作用（包括营养素、食物成分和物质， 添加剂和防腐剂），我们将使用多种健康的饮食模式。系统性miR将在 在ARIC中使用最先进的小RNA-seq的血浆，将测量候选和筛选的miR 在ARIC和梅萨中使用qPCR。我们的目标是确定成本效益：1）是否整个饮食代表 通过健康的饮食模式，前瞻性地与miR相关;以及2）是否诊断前miR是 与冠心病事件的前瞻性相关性与整个饮食有关。我们将确定饮食相关和冠心病相关 来自候选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 饮食评分较高的参与者与饮食评分较低的参与者之间的冠心病风险。我们的调查结果 这项研究将阐明miR作为一种新的途径，将整个饮食与CHD事件联系起来，并将提供对以下方面的深入了解： miR作为基因饮食调节的新生物标志物和作为评估新治疗药物的替代物的用途 方法和公共卫生战略，以防止冠心病事件。

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.