Multi-omics of the Frequent Exacerbator Asthmatic

摘要 哮喘在美国是一种常见的、复杂的和昂贵的儿科慢性疾病，导致近200万人 急性护理就诊和每年820亿美元的总成本。城市低收入家庭子女 社区哮喘患病率最高，哮喘发病率差异最大， mortality.在俄亥俄州的汉密尔顿县，超过36，000名儿童患有哮喘，其中> 14，000人是医疗补助- 住院率高出10倍。哮喘加重，急性发作增加 哮喘症状和肺功能的恶化是患者和家庭压力的主要原因。 虽然急性发作是控制不良和严重哮喘的突出特征，但急性发作率 即使在轻度哮喘患者中也可以很高，并且哮喘急性发作频率可以保持不变 尽管进行了强化控制治疗事实上，儿科研究显示， 尽管基线症状控制良好哮喘的常见加重表型（定义为 2次或2次以上急性发作/年），但对该哮喘亚组知之甚少， 不成比例地影响城市人口，并造成相当大的哮喘发病率， 医疗费用。没有特定的临床特征可以可靠地区分频繁和 非频繁加重突出需要系统水平的方法。我们的中心特定项目 将填补这一理解上的空白。我们的初步数据显示， 频繁加重并突出生物学特征的儿童鼻上皮中的甲基化基因 这些通路涉及构成频繁加重表型基础的不同机制。我们将 检验假设：频繁加重是哮喘的一种独特内在型，其特征在于宿主 鼻上皮转录组学和/或DNA甲基化组学模式，区分频繁的加重因素 哮喘儿童并不是频繁的加重者，这些模式在一定程度上是由 不同的鼻腔微生物模式我们提出了一个创新的战略，利用多个系统为基础的 采用鼻上皮转录组学的方法， 急性加重期间（类固醇给药前）。我们是独一无二的准备来进行这一行动 由于我们作为俄亥俄州儿童哮喘项目的一部分建立了庞大的基础设施， 我们的多学科团队。我们研究的总体目标是改善 来自城市社区低收入家庭的哮喘儿童。我们提出两个目标：（1） 通过开展网络范围内的CAUSE临床研究项目，为CAUSE的总体目标做出贡献 并参与CAUSE指导委员会和其他网络功能;（2）开展中心- 与CAUSE目标一致的特定项目集中在频繁加重哮喘表型上。

ABSTRACT Asthma is a common, complex and costly pediatric chronic condition in the U.S., resulting in nearly 2 million acute-care visits and $82 billion in overall costs each year. Children of low-income families in urban communities have the highest prevalence of asthma and the greatest disparities in asthma morbidity and mortality. In Hamilton County, OH, over 36,000 children have asthma, >14,000 of whom are Medicaid- insured with a 10-fold higher rate of hospitalization. Asthma exacerbations, acute episodes of increased asthma symptoms and deteriorations in lung function, are a major cause of stress for patients and families. While exacerbations are a prominent feature of poorly controlled and severe asthma, exacerbation rates can be high even in patients with mild asthma and asthma exacerbation frequency can remain unchanged despite intensive controller therapy. Indeed, pediatric studies have revealed that exacerbations continue to occur despite good baseline symptom control. A frequent exacerbator phenotype of asthma (defined by 2 or more exacerbations/year), has been described, but little is known about this asthma subgroup, which disproportionately affects urban populations and is responsible for considerable asthma morbidity and healthcare costs. No specific clinical characteristics can reliably discriminate between frequent and nonfrequent exacerbators highlighting the need for systems level approaches. Our center-specific project will fill this gap in understanding. Our preliminary data reveal differentially expressed and differentially methylated genes in the nasal epithelial of children who are frequent exacerbators and highlight biologic pathways that implicate distinct mechanisms that underlie the frequent exacerbator phenotype. We will test the hypothesis: the frequent exacerbator is a distinct endotype of asthma that is characterized by host nasal epithelial transcriptomic and/or DNA methylomic patterns that distinguish the frequent exacerbator from asthmatic children who are not frequent exacerbators, and that these patterns are, in part, triggered by distinct nasal microbial patterns. We propose an innovative strategy utilizing multiple systems-based approaches that layer host nasal biome and methylome patterns with nasal epithelial transcriptomics taken during an acute exacerbation (before administration of steroids). We are uniquely poised to conduct this study due to the tremendous infrastructure that we have established as part of the Ohio Pediatric Asthma Repository, and our multidisciplinary team. The overall objective of our studies is to improve the lives of children with asthma from low-income families who live in urban communities. We propose to 2 aims: (1) To contribute to the overall CAUSE goals by conducting network-wide CAUSE clinical research projects and participating in the CAUSE Steering Committee and other network functions; (2) To conduct a center- specific project aligned with CAUSE goals focused on the frequent exacerbator asthma phenotype.