Obesity Genes, Energy Regulation in Response to Weight-Loss Diets

摘要 在饮食干预中，减肥中存在着相当大的人际差异，可能是由于个人的 固有因素，如基因组和表观基因组变异；然而，我们目前对这些的了解 这些因素都极其糟糕。拟议的系统研究旨在填补这一重大研究空白。在三年内 关于减肥饮食的独立、全面的比较试验--体重减少、直接减肥和宏观减肥， 我们建议进行到目前为止最全面的表观基因组范围关联研究(Ewas)，使用 基于捕获的最新亚硫酸氢盐测序方法(靶向~5M动态CPGS)鉴定DNA 饮食干预与长期(长达2年)体重减轻相关的甲基化(DNaM) (目标1a和1b)，并评估饮食对dNaM动态变化的影响(目标1c)。我们将发展联合 跨CpG站点整合甲基化信息的dNaM评分(MES)，并分析其与 减肥(目标2)。我们还将研究dNaM和能量平衡标记物(AIM)之间的关系 3)。此外，我们将应用最新开发的多组学算法来预测体重下降，通过整合 DNaM与基因组学、代谢组学、生化和临床措施(目标4)。我们相信我们的研究 将为表观基因组学和多重基因组学在决定减肥反应中的作用提供新的见解 饮食干预，显著提高了精准肥胖管理的效率。

Abstract Considerable interpersonal variability in weight loss exists in diet interventions, likely due to individuals' inherent factors such as genomic and epigenomic variations; however our currently knowledge on these factors is extremely poor. The proposed systems study aims to fill this significant research gap. In three independent, comprehensive comparator trials on weight-loss diets – POUNDS LOST, DIRECT and MACRO, we propose to perform thus far the most comprehensive epigenome-wide association study (EWAS) using state-of-the-art capture-based bisulfite sequencing approach (targeting ~5M dynamic CpGs) to identify DNA methylation (DNAm) associated with long-term (up to 2 years) weight loss in response to diet interventions (Aim 1a and 1b), and assess the dietary effects on dynamic changes in DNAm (Aim 1c). We will develop joint DNAm Scores (MeS) integrating methylation information across CpG sites, and analyze their associations with weight loss (Aim 2). We will also examine the relations between DNAm and markers of energy balance (Aim 3). In addition, we will apply newly-developed multi-omics algorithm to predict weight loss, by integrating DNAm with genomics, metabolomics, biochemical and clinical measures (Aim 4). We believe that our study will provide novel insights into the roles of epigenomics and multi-omics in determining weight loss in response to diet interventions, and contribute significantly to improve efficiency of precision obesity management.