Transcriptomic and Pharmacogenetic Asthma Endotypes in Minority Children

项目总结 哮喘影响着世界5%的人口。在美国，拉丁美洲人的哮喘死亡率高出四倍， 非裔美国人与白人的对比。儿童哮喘是一种复杂的疾病，历史上部分定义为 临床特征重叠。然而，在临床疾病和呼吸道病理中观察到的异质性 建议哮喘的标准定义由多个临床亚组组成，每个亚组都有不同的 发病机制(即内型)。支气管呼吸道刷检的基因表达谱鉴定为2型- 高哮喘内型，定义为由2型细胞因子驱动的过度呼吸道炎症。我们发现， 通过微创鼻道的基因表达谱可识别2型高哮喘内型 上皮刷。我们还发现，鼻部高表达2型细胞因子IL-13与 波多黎各人哮喘发作的风险较高，他们的哮喘发病率和死亡率是#年最高的 美国哮喘发病率最高的人群对大多数哮喘的反应也是最差的 常见的哮喘药物沙丁胺醇。我们假设特定的分子呼吸道内型将定义 患有严重哮喘和药物反应差的儿童，这些内型会有很强的遗传 基础。为了研究这一假说，提出了以下目标：(1)确定表达内型 儿童哮喘是沙丁胺醇药物反应差和严重疾病的基础，使用微创 样本。通过对整个转录组的计算分析进行分子内切分型 来自745名哮喘和健康儿童的测序数据。呼吸道内型的相关性将是 用外周血基因表达鉴定。(2)确定IL-13如何改变呼吸道细胞的反应 沙丁胺醇和HRV感染，以及这些反应的遗传控制。一种功能强大的体外呼吸道上皮细胞 模型将被用来确定呼吸道上皮2型炎症是否改变转录 对沙丁胺醇(最常见的哮喘药物)和人类鼻病毒(HRV)感染(最常见)的反应 引发哮喘发作)。(3)确定和验证药物反应差和重症的遗传基础 不同种族儿童的哮喘内型。我们将进行第一次2-高的基因筛查 其他哮喘内型。我们将检查4379名患有哮喘的少数民族儿童的数据，以确定如何 哮喘内型影响对沙丁胺醇的反应和严重哮喘的风险。我们的目标是了解 哮喘严重程度和肺功能的种族/民族差异的遗传基础。这项提案的结果将是 为公共卫生政策和临床实践提供信息，并帮助从机制上了解哮喘的严重程度 (发病率)，这可能导致更有针对性的治疗。我们的建议书生成的数据将成为 为医学界和科学界提供宝贵的资源。

PROJECT SUMMARY Asthma affects 5% of the world population. In the U.S., asthma death rates are four-fold higher in Latinos and African Americans compared to Whites. Childhood asthma is a complex disease historically defined by partially overlapping clinical features. However, the heterogeneity observed in clinical disease and airway pathology suggests that the standard definition of asthma is composed of multiple clinical subgroups each with a distinct pathogenesis (i.e. endotypes). Gene expression profiling of bronchial airway brushings identified the type 2- high asthma endotype, defined by excessive airway inflammation driven by type 2 cytokines. We found that the type 2-high asthma endotype can be identified by gene expression profiling of minimally invasive nasal airway epithelium brushings. We also found high nasal expression of the type 2 cytokine, IL-13, was associated with higher risk of asthma attacks among Puerto Ricans, who have the highest asthma morbidity and mortality in the U.S. The populations with the highest asthma morbidity also have the poorest response to the most common asthma medication, albuterol. We hypothesize that specific molecular airway endotypes will define children with severe asthma and poor drug response and that these endotypes will have a strong genetic basis. To investigate this hypothesis the following aims are proposed: (1) Determine the expression endotypes of childhood asthma that underlie poor albuterol drug response and severe disease, using minimally invasive samples. Molecular endotyping with be performed by computational analysis of whole transcriptome sequencing data generated from 745 asthmatic and healthy children. Correlates of airway endotypes will be identified using peripheral blood gene expression. (2) Determine how IL-13 modifies airway cell responses to albuterol and HRV infection, and the genetic control of these responses. A powerful in vitro airway epithelial model will be used to determine if type 2 inflammation of the airway epithelium modifies transcriptional response to albuterol (most common asthma medication) and human rhinovirus (HRV) infection (most common trigger of asthma attacks). (3) Determine the genetic basis of and validate poor drug response and severe asthma endotypes in ethnically diverse children. We will perform the first genetic screen of type 2-high and other asthma endotypes. We will examine data from 4,379 minority children with asthma to determine how asthma endotypes influence response to albuterol and risk for severe asthma. Our goal is to understand the genetic basis of racial/ethnic differences in asthma severity and lung function. Results from this proposal will inform public health policy and clinical practice and aide in the mechanistic understanding of asthma severity (morbidity), which may lead to more targeted therapies. Data generated from our proposal will become a valuable resource for the medical and scientific communities.