Puerto Ricans (PRs) share a disproportionate burden of childhood asthma in the United States. Although genome-wide association studies (GWAS) have identified genetic variants associated with asthma and lung function, such variants explain a small proportion of the heritability of these complex traits. The next step is to identify epigenetic and transcriptomic risk markers for asthma and lung function, and to understand how they jointly influence these traits in children. However, most epigenomic and transcriptomic studies of asthma have thus far focused on blood. DNA methylation and gene expression in nasal (airway) epithelium are well correlated with those in bronchial (airway) epithelium, and sampling nasal epithelial cells is safer and more cost-effective than conducting bronchoscopies for studies of airway epithelium and asthma in children. We recently showed promising results in an epigenome-wide association study (EWAS) of childhood asthma using DNA from nasal (airway) epithelium. Despite their facts, nasal ?omics? data are rarely available and not included in the Genotype-Tissue Expression (GTEx) database. From 2006 to 2019, we used funding from NIH grants HL079966 and HL117191, as well as internal resources, to obtain genome-wide (GW) genotypic data, as well as GW DNA methylation and GW gene expression data in nasal epithelium, in a well-characterized cohort of Puerto Rican children and adolescents (aged 9 to 20 years) who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study (EVA-PR). Using data generated for EVA-PR and other studies, we have conducted: 1) a meta-analysis of GWAS of asthma in Puerto Ricans, 2) a GWAS of lung function in children with asthma, 3) an EWAS of serum total IgE in Hispanic children, and 4) an EWAS of atopy and atopic asthma in nasal epithelium from Puerto Rican children, with replication in two independent cohorts. On the basis of our preliminary studies, we hypothesize that understanding complex interaction among multi-omics data in nasal epithelium will further reveal epigenomic and transcriptomic profiles that are associated with asthma and lung function in Puerto Rican children and in children in other ethnic groups. To test this hypothesis, we will use an approach integrating our ?omics? data from nasal epithelium in EVA-PR with ancestry inference and an admixture mapping analysis. In particular, we will perform admixture mapping and integrate association signals for asthma and lung function measures with analyses of GW genotypic data, and GW DNA methylation and GW gene expression data from nasal epithelium in Puerto Rican children (Specific [Sp.] Aim 1). We will then examine the interplay among multi-omics data and quantify their relative contributions to asthma and lung function measures in Puerto Rican children (Sp.
Aim 2). This proposal should identify markers of asthma and lung function in a high-risk population (Puerto Rican children), and advance our knowledge of the pathogenesis of asthma, which will ultimately help us develop new methods to prevent or treat childhood asthma in general, and in Puerto Ricans in particular.
This proposal is expected to identify genetic, epigenetic variants and transcriptomic markers that influence lung function or asthma in Puerto Rican children. Such findings should increase our understanding of asthma, and ultimately help us develop new approaches to prevent and treat childhood asthma in Puerto Ricans, possibly for other ethnic groups.