Early Life DNA Methylation and Childhood Allergic Disease

描述（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。生命早期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赋予风险，基因表达的遗传变化不会直接改变DNA序列。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，它们处于环境和基因表达的界面。然而，目前尚不清楚这些变化是导致疾病的原因还是疾病的次要结果。无论机制如何，在易于获取的材料（如来自脐带血的DNA）上发现疾病与甲基化模式之间的相关性是很重要的，因为它可能作为疾病易感性的生物标志物。这项应用的总体假设是，早期发生的DNA甲基化变化会影响

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.