ABSTRACT Genes associated with asthma are often expressed in airway epithelium, and such epithelium regulates immune responses to environmental challenges and airway inflammation. Thus, epigenetic regulation and gene expression in airway epithelium could be key to asthma pathogenesis. Indeed, we recently identified biologically plausible DNA methylation and transcriptomic markers of atopic asthma in airway (nasal) epithelium of children and adolescents of Puerto Rican, African American, and European descent. Such markers are located in or near genes related to immune regulation and airway epithelial integrity and function, yet most were not identified by GWAS. Moreover, we developed nasal methylation and transcriptomic profiles that accurately classified subjects by atopic asthma in a cross-sectional study. In contrast to these findings in children, little is known about the underlying mechanisms or predictors of asthma in Hispanic adults, including Puerto Rican and Dominican adults. Lack of such knowledge is an important problem, because, without it, gaining the ability to prevent or treat asthma morbidity in this underserved group is highly unlikely. The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) provides a unique opportunity to examine DNA methylation and gene expression in airway epithelium and asthma, lung function, and asthma outcomes in Puerto Rican and Dominican adults. On the basis of our novel preliminary results, we hypothesize that altered expression of genes that regulate airway epithelial function and immune responses are associated with asthma, lung function, and asthma severity or control in Puerto Rican and Dominican adults. To test this hypothesis, we will first conduct a genome-wide (GW) study of association between DNA methylation in nasal (airway) epithelium from 900 Puerto Rican and Dominican adults in HCHS/SOL and asthma, lung function and lung function decline, and asthma control or severity, and develop predictive or classification models of asthma outcomes (Sp. Aim 1). We will then perform a GW study of association between gene expression in nasal epithelium in the same subjects as in Sp. Aim 1 and asthma, lung function and lung function decline, and asthma control or severity, and develop predictive or classification models of asthma outcomes. Next, we will conduct expression quantitative trait locus (eQTL) analysis and expression quantitative trait methylation (eQTM) analyses to integrate the results from available GW genotypic data with those from the analyses of methylation and expression (conducted in Sp. Aims 1 and 2), and perform a pathway analysis and functional validation studies for the top genes. This proposal will address an important, yet unstudied, aspect of asthma ?omics?: the identification of epigenomic and transcriptomic markers and/or determinants of asthma outcomes among adults in two Hispanic subgroups at intermediate to high risk of asthma (Dominicans and Puerto Ricans). To achieve this goal, we have assembled an outstanding multidisciplinary research team.
|Effective start/end date||6/1/21 → 5/31/22|
- National Heart, Lung, and Blood Institute: $699,612.00
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