Early Life DNA Methylation and Childhood Allergic Disease

生命早期 DNA 甲基化和儿童过敏性疾病

基本信息

批准号：
8792239
负责人：
DAWN L DEMEO
金额：
$ 71.28万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792239
关键词：
7 year old Affect Age Air Pollution Allergic Allergic Disease Allergic rhinitis Antioxidants Archives Asthma Biological Markers Birth Blood specimen Cells Child Childhood Chronic Disease DNA DNA Methylation DNA Sequence Detection Developed Countries Development Diet Disease Disease susceptibility Eczema Environment Environmental Exposure Environmental Risk Factor Epigenetic Process Exposure to Folic Acid Gene Expression Generations Genes Genome Health Hematological Disease Hypersensitivity IgE Intake Life Mediator of activation protein Meta-Analysis Methods Methylation Modeling Modification Molecular Newborn Infant Outcome Pattern Perinatal Perinatal Exposure Phenotype Predisposition Prevalence Prevention Measures Reporting Research Research Personnel Risk Sampling Site Smoking Testing Time Transcriptional Regulation Umbilical Cord Blood Validation Vitamin E ambient air pollution bead chip cohort dietary supplements disorder risk early life exposure epigenetic marker epigenome genome wide methylation high risk in utero maternal cigarette smoking methylation pattern novel postnatal prenatal prenatal exposure prevent primary outcome programs prospective public health relevance pyrosequencing screening secondary outcome

项目摘要

DESCRIPTION (provided by investigator): Allergic disorders, such as asthma and eczema, are the most common chronic diseases of childhood in developed countries. Early life and prenatal exposures contribute to the development of these disorders. Pre- and perinatal exposures may confer risk through epigenetic mechanisms, heritable changes in gene expression that occur without directly altering the DNA sequence. While there are several epigenetic mechanisms, DNA methylation is most commonly studied, and the methylation state at certain sites may affect gene activity and expression. Epigenetic patterns are sensitive to environmental exposures and they lie at the interface of the environment and gene expression. It remains unclear, however, whether such changes are causal for disease or whether they are a secondary outcome of the disease. Regardless of mechanisms, finding correlations between disease and methylation patterns on easily accessible materials (such as DNA from cord blood) is important due to the potential utility as biomarkers of disease susceptibility. The overall hypothesis of this application is that DNA methylation changes that occur in early life will affect the risk for developing allergic disorders in childhood, and that epigenetic signatures in cord blood DNA can be used as a biomarker for these childhood outcomes. We will conduct studies to test this hypothesis in a longitudinal birth cohort, Project Viva, in which we have extensive information on prenatal diet and other exposures, cord blood DNA samples collected at birth, and allergic outcomes in childhood. After the screening and validation, we will perform replication studies in two separate birth cohorts: MeDALL(Mechanisms of the Development of Allergy) and Generation R. Our specific aims are: (1) to identify novel regions in the epigenome that are differentially methylated in allergic versus non-allergic children. We will use a high-throughput genome-wide methylation panel and cord blood DNA samples in ~700 subjects from Project Viva and determine regions that are differentially methylated in children with and without allergic outcomes at 7 yrs. of age, and replicate these findings in MeDALL and Generation R. Pyrosequencing will be used to validate associated methylation marks in cord blood, and to assess longitudinal stability of the marks in DNA from ages 3 and 7. (2) To examine whether prenatal exposures such as prenatal diet (antioxidants, primarily vitamin E), maternal smoking, and exposure to ambient air pollution affect differential methylation of genes related to allergic outcomes. (3)To examine whether post-natal exposures such as child's diet, supplement intake, and exposure to air pollution modify the association between differential methylation in cord blood DNA and allergy outcomes in childhood. Our project uses state-of-the-art epigenetic screening methods in 3 prospective longitudinal birth cohorts; such an approach may identify an epigenetic signature programmed in utero that predicts allergic outcomes in childhood, which could allow for more timely and targeted detection and prevention measures.

描述（由研究人员提供）：过敏性疾病，例如哮喘和湿疹，是发达国家最常见的童年慢性疾病。早期生活和产前暴露有助于这些疾病的发展。围产期和围产期暴露可能通过表观遗传机制赋予风险，基因表达的可遗传变化，而基因表达不直接改变DNA序列。尽管有几种表观遗传机制，但最常见的是DNA甲基化，并且某些位点的甲基化状态可能会影响基因活性和表达。表观遗传模式对环境暴露敏感，它们位于环境和基因表达的界面。但是，尚不清楚这种变化是疾病的因果关系还是疾病的次要结果。不管机制如何，由于潜在的疾病易感性生物标志物的潜在效用，因此在易于获得的材料（例如脐带血的DNA）上找到疾病与甲基化模式之间的相关性很重要。该应用的总体假设是，早期生命中发生的DNA甲基化变化将影响在童年时期出现过敏性疾病的风险，以及脐带血DNA中的表观遗传学特征可以用作这些童年结局的生物标志物。我们将在Viva项目中进行研究，以检验该假设，其中我们拥有有关产前饮食和其他暴露的广泛信息，出生时收集的脐带血DNA样本以及童年时期的过敏结果。在筛选和验证后，我们将在两个单独的出生队列中进行复制研究：奖章（过敏的发育机制）和R代。我们的具体目的是：（1）鉴定表观基因组中在过敏性与非过敏性儿童中差异化甲基化的新型区域。我们将使用来自Project Viva的约700名受试者中的高通量基因组甲基化面板和脐带血DNA样品，并确定在7岁时有或没有过敏性结果的儿童中差异化甲基化的区域。年龄的年龄，并在奖章和R.一代中复制这些发现，将使用旋际测序来验证脐带血中相关的甲基化标记，并评估3岁和7岁的DNA中标记的纵向稳定性。与过敏性结果有关的基因。（3）检查产后暴露，例如儿童饮食，补充摄入量和暴露于空气污染是否改变了脐带血DNA中差异甲基化与儿童过敏结果之间的关联。我们的项目在3个前瞻性纵向出生队列中使用最先进的表观遗传筛查方法；这种方法可能会确定子宫中编程的表观遗传学签名，该签名可以预测儿童期过敏性结果，这可以允许更及时，有针对性的检测和预防措施。