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.
Environmental exposures have been shown to have a great impact on the development of allergic/atopic disorders and epigenetic mechanisms such as DNA methylation have been proposed as mediators of the environmental effects. In this study, we propose to identify epigenetic markers in cord blood samples that may predict which children will develop allergic disorders. In doing so, we may be able to determine ways in which to prevent the development of allergic disorders.
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