Social adversities, epigenetics, and the obesity epidemic

项目摘要。本申请是根据PAR-16-355《社会表观基因组学》提交的 研究重点是少数民族健康和健康差距(R01)，以及这一总体长期目标 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 保护少数群体，减少健康差距。这笔赠款旨在解开社会 逆境增加了年轻人肥胖的风险。肥胖被选为主要的健康结果，因为它是一种健康 在过去30年里，种族/民族差距不断扩大，这是一个强有力的预测因素 在晚年的社会、教育、职业和健康方面的许多负面后果。在这项研究中，我们建议 利用佛罗里达州和北卡罗来纳州正在进行的两个产前队列，招募470名孕妇样本 妇女和跟随她们的孩子到24个月大。样本将被丰富，以应对怀孕期间的逆境 在高加索人、非裔美国人和西班牙人中大致平均分配。我们将评估 孕期应激对人脐静脉内皮细胞DNA甲基化的影响 细胞(HUVEC)，就细胞组成而言是同质的，并被广泛接受为最佳 选择检查子宫内对应激源的反应。在表观遗传学分析中，我们将同时使用靶向和 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 (DMRS)调节~90个已知印迹基因，以及Illumina Human MylationEPIC(850k)珠芯片 进行完整的表观基因组分析。我们还将评估母婴产后心理社会压力。 在生命的前24个月，暴露和儿童的成长。在儿童时期的任何时候都超重的儿童 生命的头两年在五岁时患肥胖症的风险大约增加六倍，而 整个生命周期的慢性健康问题。这项研究的主要假设建立在前期工作的基础上 来自我们小组的研究包括：1)母亲产前应激将与增加的DMR调节 印迹基因胰岛素样生长因子2和母体表达基因3的表达 DMR，钙/钙调蛋白依赖性蛋白激酶IV(CAMK4)基因甲基化增加，以及 850K分析中发现的新CpG位点的甲基化变化；2)DNA甲基化图谱的变化 与产前应激有关的基因表达变化；以及3)甲基化标志物 在目标1中确定的将预测24个月大时的生长轨迹和肥胖测量。次要的 分析将审查几个缓和因素，包括：母亲的不良童年经历(ACE)， 母体社会支持、母体产后心理社会苦恼、产后子代ACE、遗传变异、 以及相关的混杂变量。还将探讨炎症标志物的中介作用，以及 唾液DNA样本将在24个月大的婴儿和50个婴儿出生时在整个队列中收集，从而允许 检测HUVEC和唾液中DNA甲基化的可比性，以及标记随时间的稳定性。

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.