Aberrant DNA Methylation Underlying Prenatal Exposures and Increased Newborn and Childhood Adiposity

项目摘要 儿童肥胖和随之而来的不良代谢健康的起源可能始于子宫。这个 高血糖和不良妊娠结局随访研究(HAPO FUS)提供了实质性的 有证据表明，孕妇怀孕期间的高血糖和BMI与肥胖密切相关 他们10到14岁的孩子。然而，作为调节该途径的机制，存在着知识鸿沟 不良的子宫环境和儿童肥胖发展之间的关系尚未阐明。 不良子宫环境引发的表观遗传DNA改变可能是一种机制 母亲高血糖/肥胖与儿童肥胖之间的潜在联系。我们假设 异常的后代DNA甲基化是对不利的宫内环境的反应， 以母体高血糖和/或肥胖为特征。差异DNA甲基化(DNaM)可能 影响代谢的重要基因，导致肥胖的胎儿程序化，以及更高的 儿童肥胖症。为了调查这些重要的问题，我们将利用HAPO FUS 我们有关于子宫环境的详细信息的队列，直接测量 新生儿和儿童肥胖症以及现有的遗传数据。利用储存的脐带血和儿童的DNA 3243 HAPO FUS参与者，这项计划的目标是利用 甲基化EPIC 850K珠片(Illumina Infinium)在目标1中，我们将研究脐带血dNaM 选择候选基因，建议在母亲高血糖/BMI与新生儿和 Hapo fus儿童肥胖的结局。潜在的甲基化相关机制 将使用调解分析来确定关联。在目标2中，我们将整合脐带血dNaM图谱 以及来自HAPO全基因组关联研究的现有SNP数据与甲基化图谱 数量性状基因座(MQTL)以阐明与CpG相关的CpG位点的遗传结构 后代肥胖的特征。然后，我们将执行两步孟德尔随机化，以确定因果CpG基因座。 在目标3中，我们将对脐带血DNA进行表观基因组范围的关联研究，以便发现 将不利的母体环境与后代肥胖联系起来的新基因。复制重要的dNaM HAPO FUS的结果将在Gen3G队列中进行，以确保这一结果的重复性和严谨性 求婚。在评估干预措施是否有效时，特定基因的甲基化可作为生物标志物 很有效。新生物标志物的发现将使原始预防策略能够遏制恶性 代际肥胖的循环。

Project Summary The origins of childhood obesity and subsequent poor metabolic health may begin in utero. The Hyperglycemia and Adverse Pregnancy Outcome Follow Up Study (HAPO FUS) provides substantial evidence that maternal hyperglycemia and BMI during pregnancy are strongly associated with obesity in their 10-14 year old children. However, a knowledge gap exists as mechanisms mediating the pathway between an adverse uterine environment and childhood obesity development have not been elucidated. Epigenetic DNA alterations triggered by an adverse uterine environment is a possible mechanism underlying associations between maternal hyperglycemia/obesity and childhood obesity. We hypothesize that aberrant offspring DNA methylation occurs in response to an adverse intrauterine environment, characterized by maternal hyperglycemia and/or obesity. Differential DNA methylation (DNAm) may affect metabolically-important genes contributing to fetal programming of adiposity, and higher rates of childhood obesity. To investigate these important questions, we will take advantage of the HAPO FUS cohort on whom we have detailed information about the uterine environment, direct measurements of newborn and childhood adiposity, and existing genetic data. Using stored cord blood and childhood DNA of 3243 HAPO FUS participants, the goals of this project are to conduct DNA methylation studies utilizing the MethylationEPIC 850K BeadChip (Illumina Infinium). In Aim 1, we will investigate cord blood DNAm in select candidate genes proposed to play a critical role linking maternal hyperglycemia/ BMI to newborn and childhood adiposity outcomes in HAPO FUS. Potential methylation-related mechanisms underlying these associations will be identified using mediation analysis. In Aim 2, we will integrate cord blood DNAm profile and existing SNP data from the HAPO genome-wide association study with mapping of methylation quantitative trait loci (mQTL) in order to elucidate the genetic architecture of CpG sites associated with offspring adiposity traits. We will then perform 2-step Mendelian randomization to identify causal CpG loci. In Aim 3, we will conduct epigenome-wide association studies on cord blood DNA to enable discovery of new genes linking an adverse maternal milieu with offspring adiposity. Replication of significant DNAm findings from HAPO FUS will be conducted in the Gen3G cohort to ensure reproducibility and rigor of this proposal. Methylation in specific genes may serve as biomarkers when evaluating if interventions are effictive. Discovery of novel biomarkers will enable primordial prevention strategies to curtail the vicious cycle of transgenerational obesity.