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机制有显着影响，但其中许多因素的确切机制仍然知之甚少。表观遗传学是指基因功能的可遗传变化，不依赖于 DNA 序列变异，包括通过甲基化对 DNA 进行共价修饰。表观遗传因素提供了一种可遗传、可逆和动态的机制，用于调节基因表达，以响应生活方式/环境（包括营养）引起的外部刺激。在这项研究中，我们建议探索心血管疾病进展过程中发生的表观遗传变化，重点关注膳食摄入作为老年人流行病学队列（心血管健康研究（CHS））中的中介因素。具体来说，我们将调查： 目标 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）风险增加相关？目标 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）风险增加相关？目标 3：在调整其他 CVD 危险因素（例如高血压和糖尿病、亚临床疾病以及与 CVD 风险相关的行为/因素）之前和之后，DNA 甲基化是否与饮食摄入相关？关联是独立的还是甲基化似乎与 CVD 相关？目标 4：饮食因素与患有和未患有 CVD 患者的表观遗传漂变有何关系？饮食摄入量的变化是否与 DNA 甲基化的变化相对应？甲基化的变化是否介导与 CVD 的关联？我们将测量 500 名 CHS 参与者储存的血液样本中 30 个预先选定的位点的 DNA 甲基化，这些位点先前已被证明与 CVD 疾病相关。为了测量表观遗传漂移，将对间隔 6 年采集的血液样本进行 DNA 甲基化分析，以与 CHS 临床评估期间进行的食物频率调查问卷相对应。疾病结果将包括总死亡率和心血管死亡率、心肌梗死、心绞痛、心力衰竭和中风。待评估的膳食数据将包括估计的碳水化合物质量，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、炸鱼和酒精。将使用 Cox 比例风险回归评估 CVD 发生率和死亡率，并使用多元线性回归和降序回归评估饮食摄入的连续测量。模型将针对其他 CVD 危险因素进行调整，以评估饮食在表观遗传漂移和 CVD 中的作用。结果将有助于更好地理解控制表观基因组变异的机制，从而识别与疾病相关的关键改变，这些改变最终可能成为新治疗的目标。 公共卫生相关性：DNA 甲基化代表一种受环境暴露影响的基因调控机制，可能与具有遗传性和环境因素的复杂疾病有关。在这项研究中，我们将利用心血管健康研究 (CHS) 中收集的数据来研究 DNA 甲基化与心血管疾病 (CVD) 之间的关联，重点关注饮食摄入的作用，并对存储的 DNA 进行新的分析。通过研究特定位点的甲基化与营养摄入之间的关联，我们可以评估“表观遗传漂移”并更好地了解CVD进展中涉及的发病机制和机制。

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.