Nasal epithelial epigenomics and transcriptomics and asthma in Hispanic adults

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.

Grant Number: 5R01HL152475-05
NIH Institute/Center: NIH
Principal Investigator: Juan Celedon