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

项目摘要/摘要 波多黎各人的哮喘患病率为37%，白人为12%，但大多数研究已经进行 在后者中。这种哮喘负担延伸到哮喘发病率和死亡率，分别是2.4倍和4倍 波多黎各人的这一比例分别高于白人。严重的，严重的， 早期病毒性呼吸道疾病和儿童反复喘息和哮喘的发展。然而，几乎没有 已经知道了这些联系背后的机制。出生时和第一次出生时是否存在呼吸道功能障碍 早期表现为对呼吸道病毒感染的严重疾病，后来表现为儿童时期 哮喘?或者，严重的早期呼吸道疾病是否会损害正常的呼吸道，并在以后引发哮喘 童年？我们将研究波多黎各儿童，通过三个具体目标解决这些问题。目标1： 招募3000名新生儿纵向研究早期病毒性呼吸道疾病对 鼻腔呼吸道分子内型与反复喘息的风险。我们将每年收集环境，社会， 和每个参与者的临床数据，并跟踪从出生到3岁的所有呼吸道疾病。我们将记录 每个儿童疾病中喘息的严重程度和存在情况，并收集鼻拭子以确定 与这些疾病相关的病毒的存在/类型。目标2：确定重症肺炎的病毒和遗传决定因素 早期呼吸道疾病以及出生时鼻呼吸道上皮的分子状态是否 预示着这些严重的疾病。我们将对鼻呼吸道拭子进行转录和病毒分析 从受试者出生时和呼吸系统疾病期间。我们将测试严重的呼吸道疾病是否与 一般感染病毒和/或感染特定病毒种类。我们将使用全基因组遗传 识别严重早期呼吸系统疾病的风险变异和影响呼吸道基因的变异的数据 出生时和患病期间的表达(EQTL)。我们将测试顶级风险之间的GxE交互作用 变异/eQTL与不同病毒种类的感染。我们还将确定对轻度疾病的基因表达反应 比较严重的早期呼吸道疾病，并确定出生时呼吸道基因表达是否可预测 儿童早期的严重呼吸道疾病。目标3：确定早期生命严重程度之间的关系 呼吸系统疾病和疾病后但哮喘前鼻腔呼吸道基因表达谱。我们将表演 对3岁受试者的鼻拭子进行转录和病毒元基因组分析。我们将 确定严重呼吸道疾病如何影响从出生到出生的呼吸道基因表达谱轨迹 童年早期。最后，我们将确定早期生活中轻微或严重的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将是最大的少数民族前瞻性研究 婴儿，[2]提供关于严重呼吸道疾病的遗传/病毒风险因素的新的和开创性的信息， 和[3]确定高危人群在出生时和呼吸系统疾病后，但在出生前表现出的呼吸道内型 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.