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

摘要 在饮食干预中，减肥存在相当大的人际差异，这可能是由于个人的 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 的因素非常差。拟议的系统研究旨在填补这一重大研究空白。在三 关于减肥饮食的独立、全面的比较试验- POUNDS LOST、DIRECT和MACRO， 我们建议进行迄今为止最全面的表观基因组关联研究（EWAS）， 最先进的基于捕获的亚硫酸氢盐测序方法（靶向约5 M动态CpG），用于鉴定DNA 甲基化（DNAm）与饮食干预后长期（长达2年）体重减轻相关 (Aim 1a和1b），并评估膳食对DNAm动态变化的影响（目的1c）。我们将共同开发 DNA m评分（MeS）整合了CpG位点的甲基化信息，并分析了它们与 体重减轻（目标2）。我们还将研究DNAm和能量平衡标志物（Aim）之间的关系 3）。此外，我们将应用新开发的多组学算法来预测体重减轻， DNAm与基因组学、代谢组学、生物化学和临床测量（目标4）。我们相信我们的研究 将提供新的见解，表观基因组学和多组学的作用，在确定减肥反应 饮食干预，并有助于显着提高精确的肥胖管理的效率。

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.