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

• 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
• 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

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.

抽象的 与哮喘相关的基因通常在气道上​​皮中表达，这种上皮 调节对环境挑战和气道注入的免疫反应。那， 气道上皮中的表观遗传调节和基因表达可能是哮喘的关键 发病。确实，我们最近确定了生物学上合理的DNA甲基化和 儿童和青少年的气道（鼻）上皮的特应性哮喘的转录组标记 波多黎各，非裔美国人和欧洲血统的这样的标记位于或附近 与免疫调节和气道上皮完整性和功能有关的基因，但大多数不是 由GWAS确定。此外，我们开发了鼻甲基化和转录谱， 在横断面研究中，通过特应性哮喘精确地分类的受试者。与这些相反 在儿童中的发现，关于哮喘的基本机制或预测因素知之甚少 西班牙裔成年人，包括波多黎各人和多米尼加成年人。缺乏这种知识是 重要的问题，因为没有它，就能获得预防或治疗哮喘发病率的能力 这个服务不足的群体极不可能。拉丁美洲人的西班牙裔社区健康研究/研究 （HCHS/SOL）为检查DNA甲基化和基因表达提供了独特的机会 波多黎各和 多米尼加成年人。根据我们新颖的初步结果，我们假设改变了 调节气道上皮功能和免疫回报的基因的表达是 波多黎各人中与哮喘，肺功能和哮喘的严重程度或控制有关 多米尼加成年人。为了检验这一假设，我们将首先进行全基因组（GW）研究 来自900波多黎各人的鼻（气道）上皮中的DNA甲基化与 HCHS/SOL和哮喘中的多米尼加成年人，肺功能和肺功能下降，哮喘 控制或严重程度，并开发哮喘结果的预测或分类模型（sp。 1）。然后，我们将对鼻上皮中基因表达之间的关联进行GW研究 在与sp相同的主题中。 AIM 1和哮喘，肺功能和肺功能下降，以及 哮喘控制或严重性，并开发哮喘结局的预测或分类模型。 接下来，我们将进行表达定量性状基因座（EQTL）分析和表达 定量性状甲基化（EQTM）分析以整合可用GW的结果 基因型数据与甲基化和表达分析的数据（在Sp中进行。 目标1和2），并对顶部基因进行​​途径分析和功能验证研究。 该提议将解决哮喘“ Omics”的重要但未研究的方面：身份证明 成年人中哮喘结局的表观基因组和转录组标记和/或决定剂 在两个中间的西班牙裔亚组中，哮喘（多米尼加人和波多黎各人）的高风险。 为了实现这一目标，我们组建了一个出色的多学科研究团队。