Genetic contributions to epigenetic-defined endotypes of allergic phenotypes in children.

Asthma is a common respiratory disease, with contributions from both genes and the environment and significant heterogeneity in underlying endotypes; yet, little is known about the relative contributions of each to these endotypes. To address this gap, we used nasal mucosal cell DNA methylation (DNAm) and gene expression and genotypes for 284 children in the Urban Environment and Childhood Asthma (URECA) birth cohort. Using an unbiased data-reduction approach and 37,256 CpGs on a custom-content Asthma&Allergy array, empirical Bayesian factorization was implemented to identify three DNAm signatures that were associated with phenotypes reflecting allergic diseases (allergic asthma and allergic rhinitis), allergic sensitization (atopy) (specific and total immunoglobulin E), and/or type 2 inflammation (eosinophil count and fractional exhaled nitric oxide [FeNO]). These associations were replicated in the Infant Susceptibility to Pulmonary Infections and Asthma (INSPIRE) and the Children's Respiratory Environment Workgroup (CREW) cohorts. The genes that were correlated with each signature in URECA reflected three cardinal endotypes of asthma: inhibited immune response to microbes, impaired epithelial barrier integrity, and activated type 2 immune pathways. To estimate the genetic contributions to these signatures, we used a common set of genotypes available in the three cohorts. The joint SNP heritability of each signature was 0.21 (p = 0.037), 0.26 (p = 1.7 × 10^-8), and 0.17 (p = 7.7 × 10^-6), respectively. The heritabilities of the DNAm signatures suggest that genetic variation contributes significantly to epigenetic signatures of allergic phenotypes and that susceptibility to the development of specific endotypes of asthma is present at birth and is poised to mediate individual epigenetic responses to early-life environments.