Social adversities, epigenetics, and the obesity epidemic

项目摘要。本申请是为了回应PAR-16-355，社会表观基因组学而提交的 研究重点是少数民族健康和健康差异（R 01），以及这一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，减少健康差距。这项补助金的目的是解开社会 逆境会增加青年人肥胖的风险。肥胖被选为主要健康结果，因为它是一种健康问题。 在过去的三十年里，种族/民族差异不断扩大，这是一个有力的预测， 许多负面的社会，教育，职业和健康结果在以后的生活。在这项研究中，我们建议 利用佛罗里达和北卡罗来纳州两个正在进行的产前队列，并招募了470名孕妇样本， 妇女和跟踪他们的孩子到24个月大。样本将在怀孕期间的逆境中丰富 并且在高加索人、非裔美国人和西班牙裔受试者中大致平均分配。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），其在细胞组成方面是同质的，并被广泛接受为最佳的 用于检查子宫内对压力源的反应。在表观遗传分析中，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个已知的印迹基因，以及Illumina HumanMethylationEPIC（850 k）珠芯片 用于整个表观基因组分析。我们还将评估产妇和儿童的产后心理压力 暴露和儿童在生命的前24个月的生长。任何时候超重的儿童， 出生后的头两年，5岁时患肥胖症的风险增加了大约6倍， 在整个生命周期中的慢性健康问题。本研究的主要假设建立在前期工作的基础上 包括：1）母体产前压力将与增加的DMR相关， 印迹基因胰岛素样生长因子2（IGF 2）和母源表达基因3（MEG 3）的表达 DMR，钙/钙调蛋白依赖性蛋白激酶IV型（CAMK 4）基因甲基化增加，以及 在850 K分析中鉴定的新CpG位点的甲基化变化; 2）DNA甲基化谱变化 与产前应激相关的基因表达改变; 3）甲基化标记 目标1中确定的基因将预测24个月龄时的生长轨迹和肥胖测量。二次 分析将检查几个调节因素，包括：母亲的不良儿童经历（ACE）， 母体社会支持，母体产后心理社会困扰，产后后代ACE，遗传变异， 和相关的混杂变量。还将探讨炎症标志物的介导作用， 将在24个月和50名儿童出生时收集整个队列的唾液DNA标本， 测试HUVEC和唾液之间DNA甲基化的可比性，以及标记物随时间的稳定性。

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.