Early Life DNA Methylation and Childhood Allergic Disease

描述（由研究者提供）：过敏性疾病，如哮喘和湿疹，是发达国家儿童最常见的慢性疾病。早期生活和产前暴露有助于这些疾病的发展。产前和围产期暴露可能通过表观遗传机制带来风险，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甲基化是最常研究的，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。然而，目前尚不清楚这些变化是否是疾病的因果关系，或者它们是否是疾病的次要结局。无论机制如何，在容易获得的材料（例如来自脐带血的DNA）上发现疾病和甲基化模式之间的相关性是重要的，这是由于其作为疾病易感性的生物标志物的潜在效用。这项应用的总体假设是，在生命早期发生的DNA甲基化变化会影响 儿童期发生过敏性疾病的风险，以及脐带血DNA中的表观遗传特征可用作这些儿童期结果的生物标志物。我们将在纵向出生队列中进行研究以验证这一假设，Viva项目，其中我们有关于产前饮食和其他暴露的广泛信息，出生时收集的脐带血DNA样本以及儿童期过敏结果。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：MeDALL（过敏发展机制）和R代。我们的具体目标是：（1）确定新的区域在表观基因组中的差异甲基化过敏与非过敏儿童。我们将在来自Viva项目的约700名受试者中使用高通量全基因组甲基化面板和脐带血DNA样本，并确定7岁时有和没有过敏结果的儿童中差异甲基化的区域，并在MeDALL和R代中复制这些发现。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岁时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），母亲吸烟和暴露于环境空气污染是否影响与过敏结果相关的基因的差异甲基化。(3)To研究出生后的暴露，如儿童的饮食，补充剂的摄入和暴露于空气污染是否改变了脐带血DNA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;这种方法可以识别子宫内编程的表观遗传特征，预测儿童期的过敏结果，这可以允许更及时和有针对性的检测和预防措施。

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.