Early Life DNA Methylation and Childhood Allergic Disease

生命早期 DNA 甲基化与儿童过敏性疾病

• 批准号: 8610346
• 负责人: DAWN L DEMEO
• 金额: $ 76.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610346
• 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; Folate; 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; cohort; dietary supplements; disorder risk; early life exposure; epigenetic marker; epigenome; genome wide methylation; high risk; in utero; maternal cigarette smoking; novel; postnatal; prenatal; prenatal exposure; prevent; primary outcome; programs; prospective; public health relevance; pyrosequencing; screening; secondary outcome

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，如哮喘和湿疹，是发达国家最常见的儿童慢性病。早年的生活和产前的暴露导致了这些疾病的发展。产前和围产期暴露可能通过表观遗传机制增加风险，表观遗传机制是在不直接改变DNA序列的情况下发生的基因表达的遗传变化。虽然有几种表观遗传机制，但DNA甲基化是最常见的研究，某些位点的甲基化状态可能会影响基因的活性和表达。表观遗传模式对环境暴露很敏感，它们位于环境和基因表达的界面上。然而，目前尚不清楚这种变化是疾病的原因还是疾病的次要结果。不管机制如何，发现疾病与容易获得的材料(如脐带血DNA)上的甲基化模式之间的相关性是重要的，因为它可能用作疾病易感性的生物标记物。这一应用的总体假设是，在生命早期发生的DNA甲基化变化将影响 儿童患过敏性疾病的风险，以及脐带血DNA中的表观遗传特征可以用作这些童年结局的生物标记物。我们将在纵向出生队列Project Viva中进行研究，以验证这一假设，在该队列中，我们拥有关于产前饮食和其他暴露、出生时收集的脐带血DNA样本以及儿童过敏结果的广泛信息。在筛选和验证之后，我们将在两个不同的出生队列中进行复制研究：MeDALL(过敏发展机制)和R代。我们的具体目标是：(1)确定表观基因组中存在差异的甲基化区域，在过敏和非过敏儿童中。我们将使用高通量全基因组甲基化小组和来自Project Viva的约700名受试者的脐带血DNA样本，并确定在7岁时有和没有过敏结果的儿童中存在差异的甲基化区域。焦磷酸测序将用于验证脐带血中相关的甲基化标记，并评估3岁和7岁DNA中标记的纵向稳定性。(2)检查产前暴露，如产前饮食(抗氧化剂，主要是维生素E)，母亲吸烟，以及暴露在环境空气污染中是否会影响与过敏结果相关的基因的差异甲基化。(3)检查产后暴露，如儿童的饮食、补充剂摄入量和暴露于空气污染是否改变了脐带血DNA不同甲基化与儿童过敏结果之间的联系。我们的项目在3个预期的纵向出生队列中使用了最先进的表观遗传学筛查方法；这样的方法可能识别在子宫中编程的表观遗传学特征，预测童年时的过敏结果，这可能允许更及时和有针对性的检测和预防措施。