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Nasal epithelial epigenomics and transcriptomics and asthma in Hispanic adults

西班牙裔成人的鼻上皮表观基因组学和转录组学与哮喘

基本信息

批准号：
10415028
负责人：
Juan Carlos Celedon
金额：
$ 67.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10415028
关键词：
Abbreviations Address Adolescent Adult Affect African American Asthma Biology Bronchodilator Agents Central American Child Childhood Asthma Classification Cross-Sectional Studies DNA Methylation Data Development Disease Management Dominican Environment Epidemiology Epigenetic Process Epithelial Ethnic group European Extrinsic asthma Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genotype Goals Heredity Hispanic Hispanic Community Health Study/Study of Latinos Hispanic Populations Human Immune response Interdisciplinary Study Knowledge Lead Mediating Meta-Analysis Methylation Mexican Americans Molecular Biology Morbidity - disease rate Nasal Epithelium Nose Not Hispanic or Latino Outcome Pathogenesis Pathway Analysis Pharmacology Play Public Health Puerto Rican Quantitative Trait Loci Regulatory Pathway Research Severities Subgroup Testing Underserved Population airway epithelium airway inflammation asthma exacerbation asthma model base disease heterogeneity disorder prevention disorder risk epigenetic regulation epigenome-wide association studies epigenomics genome wide association study genome-wide genomic locus high risk immunoregulation methylation biomarker novel prevent pulmonary function pulmonary function decline response trait transcriptome transcriptomics validation studies

项目摘要

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.

摘要