Epigenetic Programming of Cardimetabolic Health during Childhood

儿童期高肥胖与II型糖尿病（T2DM）、冠状动脉粥样硬化性心脏病（CHD） 心脏病、高血压和某些癌症。先前的儿科研究表明， 胰岛素抵抗（IR）可能会放大儿童肥胖对未来心脏代谢健康的影响。 我们迫切需要了解儿童IR的预测因素以及IR如何改变 肥胖对成人疾病的发展规划。增加内分泌接触 在结构和功能发育的关键窗口期间， 导致儿童肥胖和IR的增长率。 人们对这些暴露对生长模式的影响知之甚少。我们假设童年 肥胖和IR影响DNA甲基化模式（DNAm），这些关联部分是 由EDC暴露形成。我们计划探索这些关系中的一个子集的女性在 在智利圣地亚哥进行的纵向生长和肥胖队列研究。这一特点鲜明的 队列具有广泛的暴露信息和全基因组颊细胞DNAm测定，以及 每6至12个月收集一次人体测量数据。我们将使用这些数据进行 三个新的调查。首先，我们建议评估儿童肥胖和肥胖症之间的关系。 青春期DNA有充分的证据表明体重指数和DNA之间的关联 在成年人的基因组中有数百个位点。我们提出了最大的，第一个纵向的 儿童肥胖与青少年DNA m之间的关联研究。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之间的位点特异性关联。很少有人研究过 这将是第一次在儿童中进行调查，并探讨IR如何改变儿童的DNA和IR。 肥胖与青少年DNA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 是由肥胖和IR介导的。我们广泛的纵向数据和全面的系列分析 将使我们能够识别可能有助于成年人早期生命编程的DNA模式， 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.