Epigenetic Programming of Cardimetabolic Health during Childhood

点击翻译按钮获取中文摘要

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.