Social adversities, epigenetics, and the obesity epidemic

社会逆境、表观遗传学和肥胖流行

• 批准号: 10188266
• 负责人: Cathrine Hoyo
• 金额: $ 10.01万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188266
• 关键词: 5 year old; Adolescent; African American; Age; Age-Months; Animals; Big Data; Birth; Body mass index; Ca(2+)-Calmodulin Dependent Protein Kinase; Caucasians; Cells; Child; Chronic; Confounding Factors (Epidemiology); DNA; DNA Methylation; Data; Development; Discrimination; Distress; Education; Endothelial Cells; Epigenetic Process; Exposure to; Florida; Gene Expression; Genes; Genetic Variation; Goals; Grant; Growth; Health; Health behavior; Hispanics; Human; Individual; Individual Differences; Insulin-Like Growth Factor II; Investigation; Knowledge; Learning; Life; Life Cycle Stages; Life Experience; Link; Low Birth Weight Infant; Low income; Measures; Mediating; Methylation; Modeling; Mothers; North Carolina; Obesity; Obesity Epidemic; Outcome; Overweight; Poverty; Pregnancy; Pregnant Women; Prevalence; Psychosocial Stress; Quality of life; Race; Research; Risk; Role; Saliva; Sampling; Site; Smoking; Social support; Socioeconomic Status; Specimen; Stress; Testing; Time; Umbilical vein; Work; Youth; adverse childhood events; bead chip; cohort; design; disorder risk; early life stress; epigenetic marker; epigenome; epigenomics; ethnic minority population; experience; follow-up; genetic variant; genome-wide; health disparity; health inequalities; imprint; in utero; indexing; inflammatory marker; interest; maltreated children; maternal depression; maternal imprint; methylation biomarker; minority health; novel; obesity in children; obesity risk; offspring; postnatal; prenatal; prenatal health; prenatal stress; psychosocial; pyrosequencing; racial and ethnic; racial and ethnic disparities; recruit; resilience; response; secondary analysis; sex; social; socioeconomics; stressor; trait; whole genome

Project Summary. This application is being submitted in response to PAR-16-355, Social Epigenomics Research Focused on Minority Health and Health Disparities (R01), and the overarching long-term goal of this research effort is to learn how to positively influence health trajectories, modify disease risk in racial/ethnic minorities, and reduce health disparities. This grant is designed to unravel the mechanisms by which social adversity confers risk for obesity in youth. Obesity was selected as the primary health outcome as it is a health measure with widening racial/ethnic disparities over the past three decades, and it is a potent predictor of a host of negative social, educational, vocational, and health outcomes later in life. In this study we propose to leverage two ongoing prenatal cohorts in Florida and North Carolina, and recruit a sample of 470 pregnant women and follow their children to 24 months of age. The sample will be enriched for adversity in pregnancy and approximately evenly divided among Caucasian, African American, and Hispanic subjects. We will assess the impact of mothers' prenatal stress on measures of DNA methylation in human umbilical vein endothelial cells (HUVEC), which are homogenous in terms of cellular composition, and widely accepted as an optimal choice for examining in utero responses to stressors. In the epigenetic analyses we will use both targeted and big data approaches, using pyrosequencing to measure methylation of 31 differentially methylated regions (DMRs) that regulate ~90 known imprinted genes, and the Illumina HumanMethylationEPIC (850k) bead chip for whole epigenome analyses. We will also assess maternal and child postnatal psychosocial stress exposure, and child growth in the first 24 months of life. Children who are overweight at any point during the first two years of life have an approximately six-fold increased risk for obesity at five years of age, and risk for chronic health problems across the lifecycle. The primary hypotheses of this study build on preliminary work from our group and include: 1) Maternal prenatal stress will be associated with increased DMRs regulating the expression of imprinted gene insulin-like growth factor 2 (IGF2) and maternally expressed gene 3 (MEG3) DMR, increased methylation in Calcium/calmodulin-dependent protein kinase type IV (CAMK4) gene, and methylation changes in novel CpG sites identified in the 850K analyses; 2) DNA methylation profile changes associated with prenatal stress will be related to alterations in gene expression; and 3) Methylation markers identified in Aim 1 will predict growth trajectories and measures of obesity at 24 months of age. Secondary analyses will examine several moderating factors, including: maternal Adverse Childhood Experiences (ACE), maternal social supports, maternal postnatal psychosocial distress, postnatal offspring ACE, genetic variants, and relevant confounding variables. The mediating role of inflammatory markers will also be explored, and saliva DNA specimens will be collected on the full cohort at 24-months and 50 children at birth, allowing for tests of comparability of DNA methylation between HUVECs and saliva, and the stability of markers over time.

项目摘要。本申请是为了响应 PAR-16-355，社会表观基因组学而提交的 专注于少数族裔健康和健康差异的研究 (R01)，以及该研究的总体长期目标 研究工作是学习如何积极影响健康轨迹，改变种族/民族的疾病风险 少数民族，并减少健康差距。这笔赠款旨在揭示社会 逆境会增加青少年肥胖的风险。肥胖被选为主要健康结果，因为它是一种健康问题 过去三十年中种族/民族差距不断扩大，这是一个强有力的预测 在以后的生活中会产生许多负面的社会、教育、职业和健康结果。在这项研究中，我们建议 利用佛罗里达州和北卡罗来纳州两个正在进行的产前队列，并招募 470 名孕妇作为样本 妇女并跟踪她们的孩子至 24 个月大。样本将针对妊娠逆境进行富集 白种人、非裔美国人和西班牙裔受试者大致各占一半。我们将评估 母亲产前应激对人脐静脉内皮细胞 DNA 甲基化的影响 细胞（HUVEC），其细胞组成是同质的，被广泛认为是最佳的 检查子宫内对压力源的反应的选择。在表观遗传学分析中，我们将使用靶向和 大数据方法，使用焦磷酸测序测量 31 个差异甲基化区域的甲基化 (DMR) 调节约 90 个已知印记基因，以及 Illumina HumanMmethylationEPIC (850k) 珠芯片 用于整个表观基因组分析。我们还将评估孕产妇和儿童产后社会心理压力 暴露和儿童出生后 24 个月内的生长。在此期间任何时候超重的儿童 生命的头两年，五岁时肥胖的风险增加约六倍，五岁时患肥胖症的风险增加约六倍。 整个生命周期的慢性健康问题。本研究的主要假设建立在前期工作的基础上 我们小组的研究包括： 1) 母亲产前压力与调节 DMR 的增加有关 印记基因胰岛素样生长因子 2 (IGF2) 和母源表达基因 3 (MEG3) 的表达 DMR，钙/钙调蛋白依赖性蛋白激酶 IV 型 (CAMK4) 基因甲基化增加，以及 850K 分析中确定的新 CpG 位点的甲基化变化； 2) DNA甲基化谱变化 与产前应激有关的将是基因表达的改变； 3) 甲基化标记 目标 1 中确定的目标将预测 24 个月大时的生长轨迹和肥胖程度。中学 分析将检查几个调节因素，包括：母亲不良童年经历（ACE）， 产妇社会支持、产妇产后社会心理困扰、产后后代 ACE、遗传变异、 以及相关的混杂变量。还将探讨炎症标志物的介导作用，以及 将对 24 个月大的整个队列和 50 名出生时的儿童采集唾液 DNA 样本，以便 测试 HUVEC 和唾液之间 DNA 甲基化的可比性，以及标记随时间的稳定性。