Epigenetic Basis of Obesity Induced Cardiovascular Disease and Type 2 Diabetes

说明(申请人提供)：肥胖与心血管疾病(CVD)和2型糖尿病(T2D)等多种并存疾病有关。肥胖症共病发病机制的共同特点是存在活跃的、低级别的炎症过程。根据最近出现的关于表观遗传调节在免疫和炎症反应中的重要性的证据，我们假设肥胖导致的免疫功能缺陷至少部分是由于外周血单个核细胞对脂肪组织分泌的脂肪因子和细胞因子的DNA甲基化改变所致。基于我们为这一假说提供有力支持的初步研究，我们的目标是确定肥胖患者和瘦人对照组之间的差异甲基化特征，并进一步评估这些甲基化变化是否参与肥胖相关共病的发病机制。首先，我们将采用包括两个阶段的循序渐进的选择过程(目标1)，确定肥胖患者和瘦体重对照组之间DNA甲基化不同的CpG位点。在询问了100个肥胖病例和100个瘦身对照的14,000多个基因中的27,000个甲基化位点后，我们将选择最有希望的甲基化位点在随后的阶段进行验证，300个肥胖病例和300个瘦身对照最终导致(大约)20个最可能/最重要的位点。接下来，我们将通过评估这些CpG位点甲基化的变化是否与从AIM 1收集的细胞中基因表达的变化相关来确定DNA甲基化差异对基因表达(AIM 2)的潜在下游机制。我们还将进行体外功能实验，以研究这些CpG位点的去甲基化是否可以激活基因表达。此外，我们将确定肥胖对心血管疾病和T2D危险因素的影响是否--至少部分地--由1600名受试者中这些CpG位点的甲基化变化所介导(目标3)。次级特定目标将测试(1)上述关系是否与种族和/或性别相关；(2)对超重儿童进行8个月的有氧运动干预是否会改变这些差异甲基化位点的甲基化状态。识别肥胖特定基因的甲基化变化将为进一步研究肥胖对免疫系统的影响机制提供重要的靶点，并为开发治疗不依赖体重减轻的多发性肥胖症的新疗法的可能性提供重要的靶点。 与公共卫生相关：肥胖正在成为儿童和成人的全球流行病。肥胖极大地增加了许多疾病的风险，如心血管疾病和2型糖尿病。本研究旨在确定肥胖引起的免疫和炎症反应的表观遗传学变化，并进一步评估这些变化是否与心血管疾病和2型糖尿病的风险有关。识别肥胖特定基因的表观遗传学变化将为开发新的预防方法或治疗多发性肥胖症的共病提供重要的靶点。

DESCRIPTION (provided by applicant): Obesity is associated with numerous comorbidities such cardiovascular diseases (CVD) and type 2 diabetes (T2D). The common denominator in the pathogenesis of the co-morbidities of obesity is the presence of an active, low-grade inflammatory process. In context of the recently emerging evidence on the importance of epigenetic regulation in the immune and inflammatory responses, we hypothesize that obesity induced defects in immune function is caused, at least in part, by DNA methylation changes in peripheral blood mononuclear cells in response to adipokines and cytokines secreted by adipose tissue. Based on our preliminary studies which provided strong support to this hypothesis, we aim to identify the differential methylation profiles between obese cases and lean controls and further evaluate whether these methylation changes are involved in the pathogenesis of obesity related co-morbidities. First, we will identify the CpG sites where DNA methylation differs between obese cases and lean controls employing a step-wise selection process involving 2 stages (Aim 1). After interrogation of 27,000 methylation sites in more than 14,000 genes in 100 obese cases and 100 lean controls, we will choose the most promising for validation in a subsequent stage with 300 obese cases and 300 lean controls eventually leading to the (approximately) 20 most likely/important sites. Next, we will determine the potential downstream mechanisms of DNA methylation differences on gene expression (Aim 2) by assessing whether changes in methylation of these CpG sites are associated with changes in gene expression in the cells collected from aim 1. Functional in vitro experiments will also be conducted to investigate whether demethylation of these CpG sites can activate gene expression. Furthermore, we will determine whether the effect of obesity on CVD and T2D risk factors is -at least partially- mediated by the methylation changes of these CpG sites in a total of 1600 subjects (Aim 3). Secondary specific aims will test (1) whether the above relationships are ethnicity and/or gender dependent; (2) whether 8-month aerobic exercise intervention in overweight children will change the methylation status of these differential methylation sites. Identification of methylation changes in specific genes in obesity will provide important targets for further study into the mechanisms of obesity's effect on the immune system and the potential to develop new therapies to treat multiple obesity comorbidities independent of weight loss. PUBLIC HEALTH RELEVANCE: Obesity is becoming a global epidemic in both children and adults. Obesity dramatically increases the risk of many diseases such as cardiovascular disease and type 2 diabetes. This research aims to identify obesity induced epigenetic changes in the immune and inflammatory response and further evaluate whether these changes are associated with the risk of cardiovascular disease and type 2 diabetes. The identification of epigenetic changes in specific genes in obesity will provide important targets for developing new prevention approaches or therapies to treat multiple obesity co-morbidities.