The impact of the cord blood methylome on early-onset pediatric atopic dermatitis

About This Grant

Project summary: With the growing prevalence of pediatric atopic dermatitis (AD) and subsequent food allergy, asthma and allergic rhinitis, there is an unmet need to identify early biomarkers to allow early disease-preventative interventions. Recent studies emphasize the heritable and environmental components of early-onset AD. DNA methylation (DNAm), a regulator of gene expression highly reactive to environmental exposures, is one potential mechanistic biomarker that that may work along the causal pathway. In our population birth cohort, the Wayne County, Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS), we identified differential cord-blood DNAm in children with early-onset AD compared to those without. Furthermore, we created a cord-blood poly-CpG score that differentiates those with early-onset AD, with a cross-validated AUC of 0.937. We aim to further investigate the connection between cord-blood DNAm and newborn blood spot DNAm, and early-onset AD in the context of established germline genetic and environmental AD risk factors. Using a rigorous framework, we will achieve this objective through the following Specific Aims: Aim 1: To identify and validate cord blood DNAm associated with early-onset AD in the context of in- utero environmental factors. We will use WGBS to identify and validate cord blood DNAm variation associated with early-onset AD in five birth cohorts spanning urban, suburban, and rural environments for early-onset AD and whether known AD-associated prenatal factors lie upstream in the causal pathway. We will also investigate whether methylation-based gestational age is associated with early-onset AD risk and the impact of the prenatal environment on this relationship. Leveraging our Henry Ford Health Eczema and Primary Care Clinics, we will also determine whether the cord-blood signatures for early-onset AD translate to newborn blood spot DNAm. Aim 2: To determine whether cord blood DNAm causally impacts risk of early-onset AD using Mendelian randomization. First, we will determine which of the 101 multi-ethnic GWAS established risk variants are cord blood methylation quantitative trait loci (mQTL) using an epigenome-wide analysis approach. Second, for those risk variants that are also mQTL, we will use these variants as instrumental variables to assess the causal relationship of the CpG sites with early-onset AD using one-sample Mendelian randomization methods. Aim 3: To determine the individual and joint contributions of DNAm, genetic, and prenatal environment scores to the prediction of early-onset AD. We will develop and validate poly-prenatal environmental risk scores (PERS) and poly-CpG risk scores (PCRS) for early-onset AD, and along with an existing polygenic risk score (PGRS) for AD, evaluate their separate and joint impact on early-onset AD prediction.