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

异常 DNA 甲基化是产前暴露和新生儿和儿童肥胖增加的基础

基本信息

批准号：
10318930
负责人：
Jami L Josefson
金额：
$ 45.18万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-10 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318930
关键词：
14 year old Aberrant DNA Methylation Affect Age Air Biological Biological Markers Blinded Body fat Body mass index Candidate Disease Gene Characteristics Child Childhood Clinical Cohort Studies DNA DNA Methylation DNA Sequence Alteration Data Ensure Environment Epigenetic Process Fasting Follow-Up Studies Genes Genetic Genotype Gestational Diabetes Glucose Goals Health Human Hyperglycemia Intervention Knowledge Leptin Life Link Maternal Exposure Measurement Measures Mediating Mediation Mendelian randomization Metabolic Metabolism Methylation Neonatal Newborn Infant Obesity Outcome Participant Pathway interactions Phenotype Play Plethysmography Pregnancy Prevention strategy Provider Quantitative Trait Loci Reporting Reproducibility Reproducibility of Results Research Personnel Role Site Sum Third Pregnancy Trimester Umbilical Cord Blood Uterus Woman adiponectin adverse pregnancy outcome bead chip cohort effectiveness evaluation efficacy evaluation epigenome-wide association studies fetal programming genetic architecture genome wide association study genome wide methylation genomic data glucose tolerance in utero insight intrauterine environment maternal hyperglycemia newborn adiposity novel marker obesity development obesity in children offspring offspring obesity perinatal intervention phenotypic data predictive marker prenatal exposure prevent response trait

项目摘要

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.

项目概要儿童肥胖和随后的代谢健康状况不佳的根源可能始于子宫内。这高血糖和不良妊娠结局随访研究 (HAPO FUS) 提供了大量的信息有证据表明，孕期母亲的高血糖和体重指数与肥胖密切相关他们10-14岁的孩子。然而，作为介导该途径的机制，存在知识差距不利的子宫环境与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 改变是一种可能的机制母亲高血糖/肥胖与儿童肥胖之间的潜在关联。我们假设异常的后代 DNA 甲基化是由于不利的宫内环境而发生的，其特征是母亲高血糖和/或肥胖。差异 DNA 甲基化 (DNAm) 可能影响代谢重要的基因，导致胎儿肥胖，并且更高的肥胖率儿童肥胖症。为了调查这些重要问题，我们将利用 HAPO FUS 我们拥有有关子宫环境的详细信息、直接测量的队列新生儿和儿童肥胖以及现有的遗传数据。使用储存的脐带血和儿童 DNA 3243 HAPO FUS 参与者，该项目的目标是利用甲基化EPIC 850K BeadChip (Illumina Infinium)。在目标 1 中，我们将研究脐带血 DNAm 选择在母亲高血糖/体重指数与新生儿之间发挥关键作用的候选基因 HAPO FUS 的儿童肥胖结果。这些潜在的甲基化相关机制将使用中介分析来识别关联。在目标 2 中，我们将整合脐带血 DNAm 谱以及来自 HAPO 全基因组关联研究的现有 SNP 数据以及甲基化图谱数量性状位点（mQTL），以阐明与相关的 CpG 位点的遗传结构后代肥胖特征。然后我们将执行两步孟德尔随机化来识别因果 CpG 位点。在目标 3 中，我们将对脐带血 DNA 进行全表观基因组关联研究，以发现将不良母亲环境与后代肥胖联系起来的新基因。重要 DNAm 的复制 HAPO FUS 的研究结果将在 Gen3G 队列中进行，以确保该研究的可重复性和严谨性提议。在评估干预措施是否有效时，特定基因的甲基化可以作为生物标志物有效。新型生物标志物的发现将使原始预防策略能够减少恶性疾病跨代肥胖的循环。