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

• 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
• 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

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.

项目摘要 儿童肥胖和随后代谢健康不良的起源可能开始在子宫内。的 高血压和不良妊娠结局随访研究（HAPO FUS）提供了大量 有证据表明，母亲在怀孕期间的高血糖和BMI与肥胖密切相关， 10-14岁的孩子。然而，知识差距存在的机制调解的途径， 不利的子宫环境和儿童肥胖症发展之间的关系尚未阐明。 由不利的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甲基化是对不利的子宫内环境的反应， 其特征在于母体高血糖症和/或肥胖。差异DNA甲基化（DNAm）可能 影响代谢重要的基因，有助于胎儿肥胖的编程， 儿童肥胖症为了研究这些重要问题，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。使用储存的脐带血和儿童的DNA， 3243名HAPO FUS参与者，该项目的目标是利用DNA甲基化研究， 甲基化EPIC 850 K BeadChip（Illumina Infinium）。在目标1中，我们将研究脐带血DNAm， 选择候选基因，这些基因被认为在将母体高血糖症/ BMI与新生儿联系起来方面起关键作用， HAPO FUS的儿童肥胖结局。这些潜在的甲基化相关机制 将使用中介分析来确定关联。在目标2中，我们将整合脐带血DNAm谱 和来自HAPO全基因组关联研究的现有SNP数据， 数量性状基因座（mQTL），以阐明与 后代肥胖特征然后，我们将进行2步孟德尔随机化，以确定致病CpG基因座。 在目标3中，我们将对脐带血DNA进行表观基因组关联研究，以发现 新的基因将不利的母体环境与后代肥胖联系起来。重要DNA m的复制 HAPO FUS的结果将在Gen 3G队列中进行，以确保其可重复性和严谨性。 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。新生物标志物的发现将使原始预防策略能够减少恶性肿瘤， 跨代肥胖的循环。