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：
10612480
负责人：
Juan Carlos Celedon
金额：
$ 67.56万
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/10612480
关键词：
Abbreviations 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 Epithelium Ethnic Population 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 Mediating Meta-Analysis Methylation Mexican Americans Molecular Biology Morbidity - disease rate Nasal Epithelium Nose Not Hispanic or Latino Outcome Pathogenesis Pathway Analysis Play Public Health Puerto Rican Quantitative Trait Loci Regulatory Pathway Research Severities Subgroup Testing Underserved Population airway epithelium airway inflammation asthma exacerbation asthma model 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 pharmacologic 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.

抽象的与哮喘相关的基因通常在气道上皮细胞中表达，并且这些上皮细胞调节对环境挑战和气道炎症的免疫反应。气道上皮的表观遗传调控和基因表达可能是哮喘的关键事实上，我们最近发现了生物学上合理的 DNA 甲基化和儿童和青少年气道（鼻）上皮特应性哮喘的转录组标记物波多黎各人、非裔美国人和欧洲人后裔的此类标记位于或附近。与免疫调节和气道上皮完整性和功能相关的基因，但大多数不是此外，我们还开发了鼻甲基化和转录组谱。与此相反，在一项横断面研究中，根据特应性哮喘对受试者进行了准确分类。在儿童中的研究结果中，人们对哮喘的潜在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人缺乏这种知识。重要的问题，因为如果没有它，就无法获得预防或治疗哮喘发病的能力这个服务不足的群体极不可能出现。西班牙裔社区健康研究/拉丁裔研究。 (HCHS/SOL) 提供了一个独特的机会来检查 DNA 甲基化和基因表达波多黎各人和哮喘患者的气道上皮和哮喘、肺功能和哮喘结果根据我们新颖的初步结果，我们采取了改变。调节气道上皮功能和免疫反应的基因的表达与波多黎各人的哮喘、肺功能和哮喘严重程度或控制有关为了检验这一假设，我们将首先对多米尼加成年人进行全基因组（GW）研究。 900 名波多黎各人鼻腔（气道）上皮 DNA 甲基化与多米尼加成年人 HCHS/SOL 与哮喘、肺功能和肺功能下降以及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. Aim 1) 然后我们将进行鼻上皮基因表达之间关联的 GW 研究。在与 Sp 1 和哮喘相同的受试者中，肺功能和肺功能下降，并且哮喘控制或严重程度，并开发哮喘结果的预测或分类模型。接下来，我们将进行表达数量性状位点（eQTL）分析和表达数量性状甲基化 (eQTM) 分析以整合可用 GW 的结果基因型数据以及来自甲基化和表达分析的数据（在 Sp. 目标 1 和 2)，并对顶级基因进行通路分析和功能验证研究。该提案将解决哮喘“组学”的一个重要但尚未研究的方面：识别成人哮喘结果的表观基因组和转录组标记和/或决定因素两个具有中度至高度哮喘风险的西班牙裔亚群（多米尼加人和波多黎各人）。为了实现这一目标，我们组建了一支优秀的多学科研究团队。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Air Quality Index and Childhood Asthma: A Pilot Randomized Clinical Trial Intervention.

空气质量指数和儿童哮喘：试点随机临床试验干预。

DOI：
发表时间：
2023-06
期刊：
影响因子：
5.5
作者：
Rosser, Franziska J;Rothenberger, Scott D;Han, Yueh;Forno, Erick;Celedón, Juan C
通讯作者：
Celedón, Juan C

Acculturation and asthma in Asian American adults.

亚裔美国成年人的文化适应和哮喘。

DOI：
发表时间：
2022-10
期刊：
影响因子：
0
作者：
Han, Yueh;Forno, Erick;Celedón, Juan C
通讯作者：
Celedón, Juan C

Asthma in the Americas: An Update: A Joint Perspective from the Brazilian Thoracic Society, Canadian Thoracic Society, Latin American Thoracic Society, and American Thoracic Society.

美洲哮喘：更新：巴西胸科学会、加拿大胸科学会、拉丁美洲胸科学会和美国胸科学会的联合视角。

DOI：
发表时间：
2022-04
期刊：
影响因子：
8.3
作者：
Forno, Erick;Brandenburg, Diego D;Castro;Celis;Holguin, Fernando;Licskai, Christopher;Lovinsky;Pizzichini, Marcia;Teper, Alejandro;Yang, Connie;Celedón, Juan C
通讯作者：
Celedón, Juan C

Asthma interactions between obesity and other risk factors.

肥胖与其他危险因素之间的哮喘相互作用。