Natural History of Viral Induced Airway Dysfunction and Asthma in Minority Children

项目总结/摘要 波多黎各人的哮喘患病率为37%，而白人为12%，但大多数研究都是在 在后者中。这种哮喘负担延伸到哮喘发病率和死亡率，分别为2.4倍和4倍 波多黎各人分别高于白人。在严重的， 早期病毒性呼吸道疾病以及儿童期反复喘息和哮喘的发展。不过小 人们对这些联系背后的机制是了解的。气道功能障碍是否存在于出生时和首次 在生命早期表现为病毒性呼吸道感染引起的严重疾病，后来表现为儿童期 哮喘？或者，早期严重的呼吸道疾病是否会损伤正常的气道，并在以后诱发哮喘？ 童年？我们将研究波多黎各儿童，通过三个具体目标来解决这些问题。目标1： 招募一组3,000名新生儿，纵向研究早期病毒性呼吸道疾病对新生儿的影响。 鼻气道分子内型与喘息复发的风险我们将收集每年的环境，社会， 以及每个参与者的临床数据，并跟踪从出生到3岁的所有呼吸系统疾病。我们将记录 严重程度和存在的喘息在每个孩子的疾病，并收集鼻拭子，以确定 与这些疾病相关的病毒的存在/类型。目的2：确定重症肌无力的病毒和遗传决定因素 早期呼吸道疾病以及出生时鼻气道上皮的分子状态是否 预测这些严重的疾病。我们将对鼻气道拭子进行转录组学和病毒分析 在出生时和呼吸道疾病期间。我们将检测是否与严重呼吸道疾病有关 一般的病毒感染和/或特定病毒种类的感染。我们将使用全基因组遗传学 用于识别早期严重呼吸道疾病风险变异和影响气道基因变异的数据 在出生时和患病期间的表达（eQTL）。我们将测试最高风险之间的GxE相互作用， 变异体/eQTL和不同病毒物种的感染。我们还将确定基因表达反应，以轻度 vs.严重的早期呼吸道疾病，并确定出生时的气道基因表达是否可预测 儿童早期严重的呼吸道疾病。目的3：确定早期生命严重程度与 呼吸道疾病和疾病后但哮喘前的鼻气道基因表达谱。我们将执行 从3岁受试者收集的鼻拭子的转录组学和病毒宏基因组学分析。我们将 确定严重的呼吸道疾病如何影响从出生到死亡的气道基因表达谱的轨迹。 童年早期最后，我们将确定早期轻度或重度呼吸道疾病是否预示着 3岁时反复喘息。我们的纵向出生队列[1]将是少数民族最大的前瞻性研究 婴儿，[2]提供了关于严重呼吸道疾病遗传/病毒风险因素的新的开创性信息， 和[3]确定高危人群在出生时和呼吸道疾病后，但在 哮喘发作。我们的研究将有助于阐明早期呼吸道疾病与哮喘之间的关系。

PROJECT SUMMARY/ABSTRACT Asthma prevalence in Puerto Ricans is 37% versus 12% for whites yet most studies have been conducted among the latter. This asthma burden extends to asthma morbidity and mortality, which are 2.4- and 4-fold higher among Puerto Ricans compared to whites, respectively. There is a strong association between severe, early-life viral respiratory illnesses and development of childhood recurrent wheeze and asthma. However, little is known about the mechanisms underlying these associations. Does airway dysfunction exist at birth and first manifest in early life as a severe illness in response to viral respiratory infections, and later as childhood asthma? Or does a severe, early-life respiratory illness injure a normal airway and precipitate asthma later in childhood? We will study Puerto Rican children to address these questions via three Specific Aims. Aim 1: Recruit a cohort of 3,000 newborns to longitudinally study the effects of early-life viral respiratory illnesses on nasal airway molecular endotype and risk for recurrent wheeze. We will collect yearly environmental, social, and clinical data on each participant and track all respiratory illnesses from birth to age 3. We will record severity and presence of wheezing in each child's illnesses and collect nasal swabs to determine the presence/type of virus associated with these illnesses. Aim 2: Identify viral and genetic determinants of severe early-life respiratory illnesses and whether the molecular state of the nasal airway epithelium at birth is predictive of these severe illnesses. We will perform transcriptomic and viral analyses on nasal airway swabs from subjects at birth and during respiratory illness. We will test if severe respiratory illnesses are associated with viral infection in general and/or infection with a specific viral species. We will use genome-wide genetic data to identify risk variants for severe early-life respiratory illnesses and variants influencing airway gene expression at birth and during illness (eQTLs). We will test for GxE interactions between top risk variants/eQTLs and infection with different viral species. We will also identify gene expression response to mild vs. severe early-life respiratory illnesses and determine if airway gene expression at birth is predictive of severe respiratory illness in early childhood. Aim 3: Determine the relationship between severity of early-life respiratory illness and post-illness but pre-asthma nasal airway gene expression profiles. We will perform transcriptomic and viral metagenomic analysis of nasal swabs collected from subjects at age 3. We will determine how severe respiratory illnesses affect the trajectory of airway gene expression profiles from birth to early childhood. Finally, we will determine if mild or severe respiratory illness in early life is predictive of recurrent wheeze at age 3. Our longitudinal birth cohort will [1] be the largest prospective study of minority infants, [2] provide novel and seminal information on genetic/viral risk factors for severe respiratory illnesses, and [3] identify airway endotypes that high-risk groups exhibit at birth and after respiratory illness, but prior to asthma onset. Our study will help to elucidate the relationship between early-life respiratory illness and asthma.