Epigenetics and Nutrition: DNA Methylation, Dietary Intake and CVD

描述（由申请人提供）：人们普遍认为饮食和其他生活方式因素对心血管疾病的发病有重要作用，但其中许多因素的确切机制尚不清楚。表观遗传学是指不依赖于DNA序列变异的基因功能的可遗传变化，包括DNA的甲基化共价修饰。表观遗传因子是一种可遗传的、可逆的、动态的调控基因表达的机制，以应对包括营养在内的生活方式/环境的外部刺激。在这项研究中，我们提出探索发生在心血管疾病进展中的表观遗传变化，重点关注饮食摄入作为一项具有良好特征的老年人流行病学队列心血管健康研究（CHS）的中介。具体而言，我们将调查：AIM 1：特定位点的DNA甲基化是否与老年人总死亡率，特别是心血管疾病死亡率的风险增加相关？AIM 2：特定位点的DNA甲基化是否与心血管疾病（特别是心肌梗死、心绞痛、心力衰竭和中风）发生风险增加相关？目标3:DNA甲基化是否与其他心血管疾病风险因素（如高血压和糖尿病、亚临床疾病和与心血管疾病风险相关的行为/因素）调整前后的饮食摄入有关？关联是独立的还是甲基化似乎是沿着CVD的途径出现的？目标4：饮食因素如何与心血管疾病患者和非心血管疾病患者的表观遗传漂变相关？饮食摄入量的变化是否与DNA甲基化的变化相对应？甲基化的改变是否介导了与心血管疾病的关联？我们将在500名CHS参与者的储存血液样本中测量30个预先选择的位点的DNA甲基化，这些位点先前被证明与CVD疾病相关。为了测量表观遗传漂变，将对相隔6年的血液样本进行DNA甲基化分析，以与CHS临床评估期间提供的食物频率问卷相对应。疾病结果将包括总死亡率和心血管死亡率、心肌梗死发生率、心绞痛、心力衰竭和中风。要评估的饮食数据将包括碳水化合物质量，包括血糖指数、血糖负荷和谷物纤维摄入量；膳食饱和脂肪、亚油酸和油酸（能量校正）；每周食用全谷物、蔬菜、水果、肉类、金枪鱼/其他鱼类、炸鱼和酒精。将使用心血管疾病发病率和死亡率的Cox比例风险回归，以及饮食摄入连续测量的多元线性回归和降秩回归来评估相关性。模型将根据其他心血管疾病风险因素进行调整，以评估饮食在表观遗传漂变和心血管疾病中的作用。结果将导致更好地理解控制表观基因组变异的机制，从而识别关键疾病相关的改变，最终可能成为新的治疗目标。

DESCRIPTION (provided by applicant): It is widely accepted that diet and other lifestyle factors contribute significantly to the pathogenesis of cardiovascular disease, however the precise mechanisms for many of these factors remains poorly understood. Epigenetics refers to heritable changes in gene function that are not dependent on DNA sequence variation and includes the covalent modification of the DNA by methylation. Epigenetic factors provide a heritable, reversible and dynamic mechanism for regulating gene expression in response to the external stimuli induced by lifestyle/environment including nutrition. In this study we propose to explore epigenetic changes that occur in the progression to cardiovascular disease with a focus on dietary intake as the mediator in a well-characterized epidemiologic cohort of older adults, the Cardiovascular Health Study (CHS). Specifically, we will investigate: AIM 1: Is DNA methylation of specific loci associated with an increased risk of total mortality and, specifically, cardiovascular disease mortality, in older adults? AIM 2: Is DNA methylation of specific loci associated with an increased risk of incident cardiovascular disease, specifically myocardial infarction, angina pectoris, heart failure, and stroke? AIM 3: Is DNA methylation related to dietary intake prior to and after adjustment for other CVD risk factors such as hypertension and diabetes, subclinical disease, and behaviors/factors related to CVD risk? Are association independent or does methylation appears to be along the pathway to CVD? AIM 4: How are dietary factors related to epigenetic drift in persons with and without CVD? Does change in dietary intake correspond with change in DNA methylation? Does change in methylation mediate the association with CVD? We will measure DNA methylation in 30 pre-selected loci previously demonstrated to be related to CVD disease in stored blood samples of 500 CHS participants. To measure epigenetic drift, DNA methylation will be analyzed on blood samples taken 6 years apart to correspond with the food frequency questionnaires administered during CHS clinical evaluations. Disease outcomes will include total and cardiovascular mortality, incident myocardial infarction, angina pectoris, heart failure and stroke. Dietary data to be assessed will include estimated carbohydrate quality, including glycemix index, glycemic load, and cereal fiber intake; dietary saturated fat, linoleic acid, and oleic acid (energy-corrected); and weekly servings of whole grains, vegetables, fruits, meats, tuna/other fish, fried fish, and alcohol. Associations will be evaluated using Cox proportional hazards regression for incidence of CVD and mortality, and multiple linear regression and reduced rank regression for continuous measures of dietary intake. Models will be adjusted for other CVD risk factors to assess the role of diet in epigenetic drift and CVD. Results will lead to a better understanding of mechanisms controlling epigenomic variation allowing for identification of crucial disease-related alterations that may ultimately be targeted for novel treatment. PUBLIC HEALTH RELEVANCE: DNA methylation represents a gene regulatory mechanism affected by environmental exposures that may be implicated in complex diseases with both genetic and environmental components that are heritable. In this study we will investigate associations between DNA methylation and cardiovascular disease (CVD) with a focus on the role of dietary intake using data collected in the Cardiovascular Health Study (CHS) and conducting new analysis of stored DNA. By investigating associations between methylation in specific loci and nutrient intake, we can assess "epigenetic drift" and better understand the pathogenesis and mechanisms involved in the progression to CVD.