Epigenetic Programming of Cardimetabolic Health during Childhood

儿童时期高度肥胖与患II型糖尿病(T2 DM)、冠心病的风险更高相关 心脏病、高血压和某些类型的癌症。先前的儿科研究表明 胰岛素抵抗(IR)可能放大儿童肥胖对未来心脏代谢健康的影响。 迫切需要了解儿童胰岛素抵抗的预测因素，以及胰岛素抵抗如何改变 肥胖对成人疾病发育规划的影响。增加对内分泌的暴露 在结构和功能发展的关键窗口期间的扰乱化学品(EDCs)可能是 导致儿童肥胖率和胰岛素抵抗的增长。延迟性心力衰竭的调节机制 人们对这些风险敞口对增长模式的影响知之甚少。我们假设童年 肥胖和IR对DNA甲基化(DNaM)的影响模式，以及这些关联部分地 受EDC暴露的影响。我们计划探索女性子集之间的这些关系 智利圣地亚哥正在进行的纵向生长和肥胖队列研究。这是一个很好的特征 Cohort拥有广泛的暴露信息和全基因组口腔细胞dNaM分析，以及 每6至12个月收集一次人体测量数据。我们将使用这些综合数据来进行 三项新奇的调查。首先，我们建议评估儿童肥胖症和 青春期dNaM。有充分证实的证据表明，体重指数和dNaM之间存在关联。 在成年人基因组中的数百个位置。我们提出了最大的，也是第一个纵向的 儿童肥胖症与青春期dNaM关系的研究第二，我们将确定 与儿童IR相关的青春期dNaM模式。大量研究已经确定 DNaM和T2 DM之间的部位特异性关联。很少有人研究过两者之间的关系 DNaM和IR。这将是第一次在儿童中进行调查，并探索IR如何修改 肥胖与青春期dNaM类型的关系最后，我们将调查 DNaM与儿童EDC暴露相关，并评估这些关系的程度 是通过肥胖和胰岛素抵抗来调节的。我们广泛的纵向数据和全面的一系列分析 将使我们能够识别dNaM的模式，这些模式可能有助于成人的早期生活规划 心脏代谢健康。

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.