Nasal epithelial epigenomics and transcriptomics and asthma in Hispanic adults

摘要 哮喘相关基因通常在呼吸道上皮细胞中表达，而这种上皮细胞 调节对环境挑战和呼吸道炎症的免疫反应。因此， 呼吸道上皮细胞的表观遗传调控和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可信的DNA甲基化和 特应性哮喘儿童和青少年呼吸道(鼻)上皮转录转录标志物的研究 波多黎各人、非裔美国人和欧洲人的后裔。这样的标记位于内部或附近 与免疫调节、呼吸道上皮完整性和功能相关的基因，但大多数都不是 由GWAs鉴定。此外，我们还开发了鼻甲基化和转录谱， 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的分类。与这些形成对比的是 在儿童中的发现，对哮喘的潜在机制或预测因素知之甚少 西班牙裔成年人，包括波多黎各和多米尼加成年人。缺乏这样的知识是一种 这是一个重要的问题，因为没有它，就有能力预防或治疗#年的哮喘发病率 这个服务不足的群体是极不可能的。拉美裔社区健康研究/拉丁裔研究 (HCHS/SOL)提供了一个独特的机会来检测DNA甲基化和基因表达 波多黎各人的呼吸道上皮细胞与哮喘、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，我们假设改变了 调节呼吸道上皮功能和免疫反应的基因的表达 与哮喘、肺功能和哮喘严重程度或控制有关的波多黎各人和 多米尼加成年人。为了验证这一假设，我们将首先进行一项全基因组(GW)研究 900名波多黎各人鼻(气)上皮DNA甲基化与 多米尼加成年人中的HCHS/SOL与哮喘、肺功能及肺功能下降、哮喘有关 控制或严重程度，并开发哮喘结局的预测或分类模型(SP。目标 1)。然后，我们将进行一项GW研究，研究鼻黏膜上皮基因表达之间的关系 与Sp.目的1和哮喘，肺功能和肺功能下降，和 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)的分析和表达 量化性状甲基化(EQTM)分析，以整合来自现有GW的结果 基因类型数据与甲基化和表达分析的数据(在Sp. 目标1和2)，并对顶端基因进行通路分析和功能验证研究。 这项提议将解决哮喘“组学”的一个重要但未被研究的方面：识别 成人哮喘预后的表观和转录标记物和/或决定因素 在两个有中高哮喘风险的西班牙裔亚群中(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.