Nasal epithelial epigenomics and transcriptomics and asthma in Hispanic adults

摘要 与哮喘相关的基因通常在气道上皮中表达，并且这种上皮 调节对环境挑战和气道炎症的免疫反应。因此，在本发明中， 表观遗传调控和气道上皮基因表达可能是哮喘的关键 发病机制事实上，我们最近发现了生物学上合理的DNA甲基化， 儿童和青少年气道（鼻）上皮中特应性哮喘的转录组标志物 波多黎各人，非裔美国人和欧洲人的后裔这些标记位于或靠近 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 由GWAS识别。此外，我们开发了鼻甲基化和转录组学图谱， 在一项横断面研究中，根据特应性哮喘对受试者进行准确分类。与此相反， 尽管在儿童中的发现，对哮喘的潜在机制或预测因子知之甚少， 西班牙裔成年人，包括波多黎各和多米尼加成年人。缺乏这种知识是一种 重要的问题，因为，没有它，获得预防或治疗哮喘发病率的能力， 这类服务不足的群体是极不可能的。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，检查DNA甲基化和基因表达， 波多黎各人的气道上皮与哮喘、肺功能和哮喘结局， 多米尼加成年人根据我们新的初步结果，我们假设， 调节气道上皮功能和免疫反应的基因表达是 与波多黎各人的哮喘、肺功能和哮喘严重程度或控制相关， 多米尼加成年人为了验证这一假设，我们将首先进行全基因组（GW）研究， 900名波多黎各人鼻（气道）上皮DNA甲基化与 多米尼加成年人在HCHS/SOL和哮喘、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. Aim 1）。然后，我们将进行GW研究鼻上皮中基因表达之间的关联 在与Sp.Aim 1和哮喘相同的受试者中，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。 接下来，我们将进行表达数量性状基因座（eQTL）分析和表达 定量性状甲基化（eQTM）分析，以整合来自可用GW的结果 将基因型数据与来自甲基化和表达分析的数据（在Sp. 目的1和2），并进行途径分析和功能验证研究的顶部基因。 这项建议将解决哮喘"组学"的一个重要但尚未研究的方面： 表观基因组和转录组标记物和/或成人哮喘结局的决定因素 在两个中高度哮喘风险的西班牙裔亚组中（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。

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.