Transcriptomic and Pharmacogenetic Asthma Endotypes in Minority Children

项目摘要 哮喘影响着世界人口的5%。在美国，拉丁美洲人的哮喘死亡率高出四倍， 美国黑人与白人比较儿童哮喘是一种复杂的疾病，历史上被部分定义为 重叠的临床特征。然而，在临床疾病和气道病理学中观察到的异质性 表明哮喘的标准定义由多个临床亚组组成，每个亚组具有不同的 发病机制（即内型）。支气管气道刷拭的基因表达谱鉴定了2型- 高哮喘内型，由2型细胞因子驱动的过度气道炎症定义。我们发现 2型-高哮喘内型可通过微创鼻气道的基因表达谱鉴定 上皮刷拭。我们还发现2型细胞因子IL-13的鼻内高表达与 波多黎各人的哮喘发病率和死亡率最高， 哮喘发病率最高的人群对最常见的哮喘的反应也最差。 常见的哮喘药沙丁胺醇我们假设特定的分子气道内型将定义 患有严重哮喘和药物反应差的儿童，这些内型将具有强烈的遗传 基础为了验证这一假说，我们提出了以下目标：（1）确定表达内型 沙丁胺醇药物反应差和严重疾病的儿童哮喘，使用微创 样品通过全转录组的计算分析进行分子内分型 测序数据来自745名哮喘和健康儿童。气道内型的相关性将 通过外周血基因表达鉴定。(2)确定IL-13如何改变气道细胞对 沙丁胺醇和HRV感染，以及这些反应的遗传控制。一种强大的体外气道上皮细胞， 模型将用于确定气道上皮的2型炎症是否改变了转录水平， 对沙丁胺醇（最常见的哮喘药物）和人鼻病毒（HRV）感染（最常见的 哮喘发作的诱因）。(3)确定药物反应不良和严重的遗传基础并验证 不同种族儿童的哮喘内型我们将进行第一次2型高的遗传筛查， 其他哮喘内型。我们将检查4，379名患有哮喘的少数民族儿童的数据， 哮喘内源性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。该提案的结果将 为公共卫生政策和临床实践提供信息，并帮助从机理上理解哮喘严重程度 （发病率），这可能导致更有针对性的治疗。从我们的提案中产生的数据将成为 医学和科学界的宝贵资源。

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.