Multi-omics Analysis of Childhood Asthma in Hispanics

西班牙裔儿童哮喘的多组学分析

• 批准号: 10238942
• 负责人: Juan Carlos Celedon
• 金额: $ 11.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238942
• 关键词: Abbreviations; Address; Adolescent; Affect; African American; Asthma; Biological; Blood; Bronchoscopy; Child; Childhood Asthma; Collaborations; Complex; DNA; DNA Methylation; Data; Data Set; Databases; Diagnosis; Environmental Risk Factor; Epigenetic Process; Epithelial Cells; Ethnic group; European; Extrinsic asthma; Funding; Gene Expression; Genes; Genetic; Genomic Segment; Genomics; Genotype; Goals; Grant; Heritability; Hispanics; IgE; Immunity; Intervention; Knowledge; Link; Lung diseases; Measures; Mediating; Mediation; Meta-Analysis; Methods; Methylation; Morbidity - disease rate; Multiomic Data; Nasal Epithelium; Nose; Outcome; Pathogenesis; Positioning Attribute; Prevention; Prevention approach; Public Health; Puerto Rican; Resources; Risk Marker; Sampling; Signal Transduction; Site; Study of serum; Testing; Tissues; United States; United States National Institutes of Health; Validation; Variant; Work; admixture mapping; aged; airway epithelium; ancestry analysis; atopy; cohort; cost effective; epigenetic variation; epigenome-wide association studies; epigenomics; genetic epidemiology; genetic variant; genome wide association study; genome-wide; genome-wide analysis; high risk population; improved; methylation biomarker; multidisciplinary; multiple omics; novel; novel strategies; personalized medicine; prevent; pulmonary function; racial and ethnic; trait; transcriptome; transcriptomics

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.

在美国，波多黎各人 (PR) 承担着不成比例的儿童哮喘负担。 全基因组关联研究（GWAS）已确定与哮喘和肺病相关的基因变异 函数，这些变异解释了这些复杂性状的一小部分遗传力。 识别哮喘和肺功能的表观遗传和转录组风险标记，并了解它们如何 然而，大多数哮喘的表观基因组和转录组研究都对儿童的这些特征产生了共同影响。 迄今为止，重点关注鼻（气道）上皮细胞中的 DNA 甲基化和基因表达。 与支气管（气道）上皮细胞相关，采样鼻上皮细胞更安全、更有效 研究儿童气道上皮和哮喘比进行支气管镜检查更具成本效益。 最近在一项针对儿童哮喘的表观基因组关联研究（EWAS）中显示出有希望的结果 尽管有事实，但鼻腔“组学”数据很少且无法获得。 包含在基因型组织表达（GTEx）数据库中 从 2006 年到 2019 年，我们使用了 NIH 的资助。 授予 HL079966 和 HL117191 以及内部资源，以获得全基因组 (GW) 基因型数据， 以及鼻上皮中的 GW DNA 甲基化和 GW 基因表达数据，以充分表征 参加表观遗传学研究的波多黎各儿童和青少年（9 至 20 岁）队列 波多黎各人的变异和儿童哮喘研究 (EVA-PR) 使用为 EVA-PR 生成的数据和 我们还进行了其他研究：1) 对波多黎各人哮喘的 GWAS 荟萃分析，2) 对波多黎各人哮喘的 GWAS 进行了荟萃分析 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的特应性和特应性哮喘，在两个独立的个体中复制 在我们的初步研究的基础上，我们追求理解复杂的相互作用。 鼻上皮的多组学数据将进一步揭示表观基因组和转录组谱 与波多黎各儿童和其他种族儿童的哮喘和肺功能有关。 检验这一假设，我们将使用一种方法将 EVA-PR 中鼻上皮的“组学”数据与 特别是，我们将执行混合映射和祖先推断。 将哮喘和肺功能测量的关联信号与 GW 基因型数据分析相结合，以及 波多黎各儿童鼻上皮的 GW DNA 甲基化和 GW 基因表达数据（具体 [Sp.] 目标 1)。然后我们将检查多组学数据之间的相互作用并量化它们的相关性。 对波多黎各儿童哮喘和肺功能测量的贡献（Sp. 目标 2）。 确定高危人群（波多黎各儿童）的哮喘和肺功能标志物，并推进我们的研究 了解哮喘的发病机制，这最终将帮助我们开发新的方法来预防或治疗 一般治疗儿童哮喘，特别是波多黎各人。

项目成果

Serum α-Klotho level, lung function, airflow obstruction and inflammatory markers in US adults.

美国成人血清 α-Klotho 水平、肺功能、气流阻塞和炎症标志物。

• 发表时间: 2023-11
• 影响因子: 4.6
• 作者: Han YY;Celedón JC;Forno E
• 通讯作者: Forno E

Asthma Exacerbations: The Genes Behind the Scenes.

哮喘加重：幕后基因。

• 发表时间: 2023-04-18
• 影响因子: 7.2
• 作者: Herrera;Forno, E;Celedón, J C;Pino
• 通讯作者: Pino

Differential gene expression in nasal airway epithelium from overweight or obese youth with asthma.

超重或肥胖哮喘青少年鼻气道上皮的差异基因表达。

• 发表时间: 2022-04
• 作者: Xu, Zhongli;Forno, Erick;Acosta;Han, Yueh;Rosser, Franziska;Manni, Michelle L;Canino, Glorisa;Chen, Wei;Celedón, Juan C
• 通讯作者: Celedón, Juan C

CHIT: an allele-specific method for testing the association between molecular quantitative traits and phenotype-genotype interaction.

CHIT：一种等位基因特异性方法，用于测试分子数量性状与表型-基因型相互作用之间的关联。

• 发表时间: 2021-12-11
• 作者: Yan, Qi;Forno, Erick;Celedón, Juan C;Chen, Wei;Weeks, Daniel E
• 通讯作者: Weeks, Daniel E

Heterotypic Influenza Infections Mitigate Susceptibility to Secondary Bacterial Infection.

异型流感感染可降低继发细菌感染的易感性。

• 发表时间: 2022-08-15
• 作者: Cipolla, Ellyse M;Yue, Molin;Nickolich, Kara L;Huckestein, Brydie R;Antos, Danielle;Chen, Wei;Alcorn, John F
• 通讯作者: Alcorn, John F