Multi-omics Analysis of Childhood Asthma in Hispanics

在美国，波多黎各人（PR）分担了不成比例的儿童哮喘负担。虽然 全基因组关联研究（GWAS）已经确定了与哮喘和肺结核相关的遗传变异， 功能，这些变异解释了这些复杂性状的遗传率的一小部分。下一步是 确定哮喘和肺功能的表观遗传和转录组风险标志物，并了解它们是如何 共同影响儿童的这些特征。然而，大多数哮喘的表观基因组和转录组研究 目前，主要集中在血液。鼻（气道）上皮DNA甲基化和基因表达良好， 与支气管（气道）上皮细胞相关，取鼻上皮细胞更安全， 在儿童气道上皮和哮喘研究中，比进行支气管镜检查更具成本效益。我们 最近在一项儿童哮喘的表观基因组关联研究（EWAS）中显示了有希望的结果， 鼻（气道）上皮DNA。尽管事实如此，鼻“组学”数据很少可用，而且 包括在基因型-组织表达（GTEx）数据库中。从2006年到2019年，我们使用了NIH的资金 赠款HL 079966和HL 117191以及内部资源，以获得全基因组（GW）基因型数据， 以及鼻上皮中GW DNA甲基化和GW基因表达数据， 波多黎各儿童和青少年（9至20岁）队列，他们参加了表观遗传学研究。 变异和儿童哮喘在波多黎各人的研究（EVA-PR）。使用EVA-PR生成的数据， 其他研究，我们进行了：1）一项关于波多黎各人哮喘GWAS的荟萃分析，2）一项关于 哮喘儿童的肺功能，3）西班牙裔儿童血清总IgE的EWAS，以及4） 波多黎各儿童鼻上皮中的特应性和特应性哮喘， 同伙在我们初步研究的基础上，我们假设理解复杂的相互作用 在鼻上皮的多组学数据中，将进一步揭示 与波多黎各儿童和其他种族儿童的哮喘和肺功能有关。到 为了验证这一假设，我们将使用一种方法，将我们在EVA-PR中鼻上皮的“组学”数据与 祖先推断和混合映射分析。特别是，我们将执行混合映射， 整合哮喘和肺功能测量的相关信号与GW基因型数据的分析，以及 来自波多黎各儿童鼻上皮的GW DNA甲基化和GW基因表达数据（特异性 [Sp.]目标1）。然后，我们将研究多组学数据之间的相互作用，并量化它们的相对 对波多黎各儿童哮喘和肺功能测量的贡献（特别目标2）。该提案 在高危人群（波多黎各儿童）中识别哮喘和肺功能的标志物，并推进我们的 了解哮喘的发病机制，这将最终帮助我们开发新的方法来预防或治疗哮喘。 治疗儿童哮喘，特别是波多黎各人。

Puerto Ricans (PRs) share a disproportionate burden of childhood asthma in the United States. Although genome-wide association studies (GWAS) have identified genetic variants associated with asthma and lung function, such variants explain a small proportion of the heritability of these complex traits. The next step is to identify epigenetic and transcriptomic risk markers for asthma and lung function, and to understand how they jointly influence these traits in children. However, most epigenomic and transcriptomic studies of asthma have thus far focused on blood. DNA methylation and gene expression in nasal (airway) epithelium are well correlated with those in bronchial (airway) epithelium, and sampling nasal epithelial cells is safer and more cost-effective than conducting bronchoscopies for studies of airway epithelium and asthma in children. We recently showed promising results in an epigenome-wide association study (EWAS) of childhood asthma using DNA from nasal (airway) epithelium. Despite their facts, nasal “omics” data are rarely available and not included in the Genotype-Tissue Expression (GTEx) database. From 2006 to 2019, we used funding from NIH grants HL079966 and HL117191, as well as internal resources, to obtain genome-wide (GW) genotypic data, as well as GW DNA methylation and GW gene expression data in nasal epithelium, in a well-characterized cohort of Puerto Rican children and adolescents (aged 9 to 20 years) who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study (EVA-PR). Using data generated for EVA-PR and other studies, we have conducted: 1) a meta-analysis of GWAS of asthma in Puerto Ricans, 2) a GWAS of lung function in children with asthma, 3) an EWAS of serum total IgE in Hispanic children, and 4) an EWAS of atopy and atopic asthma in nasal epithelium from Puerto Rican children, with replication in two independent cohorts. On the basis of our preliminary studies, we hypothesize that understanding complex interaction among multi-omics data in nasal epithelium will further reveal epigenomic and transcriptomic profiles that are associated with asthma and lung function in Puerto Rican children and in children in other ethnic groups. To test this hypothesis, we will use an approach integrating our “omics” data from nasal epithelium in EVA-PR with ancestry inference and an admixture mapping analysis. In particular, we will perform admixture mapping and integrate association signals for asthma and lung function measures with analyses of GW genotypic data, and GW DNA methylation and GW gene expression data from nasal epithelium in Puerto Rican children (Specific [Sp.] Aim 1). We will then examine the interplay among multi-omics data and quantify their relative contributions to asthma and lung function measures in Puerto Rican children (Sp. Aim 2). This proposal should identify markers of asthma and lung function in a high-risk population (Puerto Rican children), and advance our knowledge of the pathogenesis of asthma, which will ultimately help us develop new methods to prevent or treat childhood asthma in general, and in Puerto Ricans in particular.