Epigenetic Programming of Cardimetabolic Health during Childhood

儿童期心脏代谢健康的表观遗传编程

• 批准号: 10375181
• 负责人: Alexandra Margaret Lynn Binder
• 金额: $ 8.62万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375181
• 关键词: Epigenetic; Programming; Cardimetabolic; Health; during

High childhood adiposity has been associated with a greater risk of type II diabetes (T2DM), coronary heart disease, hypertension, and certain types of cancer in adulthood. Prior pediatric studies suggest that insulin resistance (IR) may amplify the influence of childhood adiposity on future cardiometabolic health. There is a critical need to understand predictors of childhood IR and how IR modifies the impact of adiposity on the developmental programming of adult disease. Increasing exposure to endocrine disrupting chemicals (EDCs) during critical windows of structural and functional development may be contributing to growing rates of both childhood obesity and IR. The mechanism mediating the prolonged influence of these exposures on growth patterns is poorly understood. We hypothesize childhood adiposity and IR impact patterns of DNA methylation (DNAm), and that these associations are partially shaped by EDC exposure. We plan to explore these relationships among a subset of females within the ongoing longitudinal Growth and Obesity Cohort Study based in Santiago, Chile. This well-characterized cohort has extensive exposure information and genome-wide buccal cell DNAm assays, as well as anthropometric measurements collected every 6 to 12 months. We will use this combined data to conduct three novel investigations. First, we propose to evaluate the association between childhood adiposity and pubertal DNAm. There is well-validated evidence of an association between body mass index and DNAm at hundreds of sites across the genome among adults. We are proposing the largest, and first longitudinal study of the association between childhood adiposity and adolescent DNAm. Second, we will identify patterns of adolescent DNAm that are associated with childhood IR. Numerous studies have identified site-specific associations between DNAm and T2DM. Far fewer have examined the relationship between DNAm and IR. This will be the first investigation among children and explore how IR modifies the relationship between adiposity and adolescent DNAm patterns. Finally, we will investigate patterns of DNAm associated with childhood EDC exposure, and evaluate the degree to which these relationships are mediated by adiposity and IR. Our extensive longitudinal data and comprehensive series of analyses will allow us to identify patterns of DNAm that may contribute to the early life programming of adult cardiometabolic health.

童年高肥胖与II型糖尿病（T2DM），冠状动脉的风险更大有关 心脏病，高血压和某些类型的癌症。先前的小儿研究表明 胰岛素抵抗（IR）可能会扩大儿童肥胖对未来心脏代谢健康的影响。 迫切需要了解儿童IR的预测指标，以及IR如何修改的影响 对成人疾病的发展编程的肥胖。增加对内分泌的接触 在结构和功能开发的关键窗口中破坏化学品（EDC）可能是 促进儿童肥胖和IR的增长速度。介导的机制 这些暴露对生长模式的影响知之甚少。我们假设童年 DNA甲基化（DNAM）的肥胖和IR撞击模式，并且这些关联是部分的 由EDC暴露塑造。我们计划探索在女性中的这些关系 正在进行的纵向生长和肥胖队列研究基于智利圣地亚哥。这个特殊的特征 队列具有广泛的暴露信息和全基因组颊细胞DNAM分析，以及 一次性测量每6到12个月收集一次。我们将使用此组合数据进行执行 三个新颖的调查。首先，我们建议评估儿童肥胖与 青春期Dnam。有充分的验证证据表明体重指数与DNAM之间存在关联 在成年人中的数百个地点。我们提出了最大，第一个纵向 研究儿童肥胖与青少年dnam之间的关联。第二，我们将确定 与儿童IR相关的青少年dnam模式。许多研究已经确定 DNAM和T2DM之间的特定地点关联。研究了少得多 DNAN和IR。这将是对儿童进行的首次调查，并探讨IR如何修改 肥胖与青少年dnam模式之间的关系。最后，我们将研究 DNAM与儿童EDC暴露相关，并评估这些关系的程度 由肥胖和IR介导。我们广泛的纵向数据和一系列分析 将使我们能够确定可能有助于成人早期生命计划的DNA模式 心脏代谢健康。