Infant blood epigenome and risks of IgE sensitization, obesity, and asthma: MARC-35/43 cohorts

项目摘要 制定儿童哮喘一级预防策略的主要挑战是： 识别可改变的风险因素（例如，表观基因组，IgE致敏，超重/肥胖）和 哮喘的异质性这个R01项目的首要目标是研究血液DNA的作用， 甲基化（DNAm）在婴儿期的发展中有三个结果：IgE致敏， 超重/肥胖（和脂肪病），并最终哮喘在两个互补的多中心前瞻性研究中 队列研究第35次多中心气道研究协作（MARC-35）研究（U01AI087881）是一项 正在进行的17个中心的队列研究，921名因细支气管炎住院的婴儿-一个高危人群， 哮喘另一项正在进行的队列研究MARC-43（UG3/UH3 OD 023253）包括600名健康婴儿。这些 种族/民族多样化的群体（52%的非洲裔美国人或西班牙裔）是真正的互补， 经历类似过程的参与者（例如，特异性IgE和细胞因子测量） (e.g.,婴儿期，3岁和6岁）。随访包括一年两次的面谈和6岁以上的医疗记录 年，迄今为止随访约90%。参与者在6岁时接受现场检查， 哮喘表型分析目前的R01项目将通过特征分析扩展这些大型特征明确的队列 1,521名婴儿的血液全基因组DNA m，然后研究他们与婴儿发育的关系。 三个主要结果：IgE致敏、超重/肥胖和哮喘。在目标1中，我们将确定 婴儿血液DNAm签名与发生哮喘的风险（包括其表型）之间的关系。我们 还将研究这些DNA m从婴儿到3岁的纵向变化，以及它们与 哮喘风险在目标2中，我们将研究婴儿血液DNAm签名与发展风险的关系。 IgE致敏和超重/肥胖（和脂肪病）。在目标3中，我们将确定IgE的作用 过敏和超重/肥胖的婴儿DNAm和哮喘之间的联系。我们的试验数据 有力地支持了这些假设。在目标4中，我们还将整合可用的多组学数据， 进一步定义目标1 - 3中确定的DNAm签名的基础机制。我们将复制我们的 来自波士顿出生队列的963名儿童的研究结果。R01项目将提供 这是一个独特的机会，可以确定IgE致敏和超重/肥胖与事件之间的联系机制。 通过研究婴儿期的DNAm--免疫和肺发育的关键时期--来研究哮喘。的 该项目还将为制定有针对性的初级预防干预措施提供强有力的证据基础 儿童哮喘

PROJECT SUMMARY The major challenges for developing primary prevention strategies for childhood asthma are the early identification of modifiable risk factors (e.g., epigenome, IgE sensitization, overweight/ obesity) and the heterogeneity of asthma. The overarching objective of this R01 project is to investigate the role of blood DNA methylation (DNAm) during infancy in the development of three outcomes: IgE sensitization, overweight/obesity (and adiposopathy), and eventually asthma in two complementary multicenter prospective cohort studies. The 35th Multicenter Airway Research Collaboration (MARC-35) study (U01AI087881) is an ongoing 17-center cohort study of 921 infants hospitalized for bronchiolitis – a population at high risk for asthma. Another ongoing cohort study, MARC-43 (UG3/UH3 OD023253), includes 600 healthy infants. These racially/ethnically-diverse cohorts (52% African American or Hispanic) are truly complementary, with participants undergoing similar procedures (e.g., specific IgE and cytokine measurements) at similar ages (e.g., infancy, ages 3 and 6 years). Follow-up includes biannual interviews and medical records to age 6+ years, with ~90% follow-up to date. Participants are undergoing in-person examination at age 6 years for asthma phenotyping. The present R01 project would extend these large well-characterized cohorts by profiling the blood genome-wide DNAm in 1,521 infants, and then examining their relations to the development of the three main outcomes: IgE sensitization, overweight/obesity, and asthma. In Aim 1, we will identify the associations of infant blood DNAm signature with the risk of developing asthma, including its phenotypes. We will also investigate the longitudinal changes of these DNAm from infancy to age 3 years, and their relations to asthma risk. In Aim 2, we will examine the relations of infant blood DNAm signature with the risk of developing IgE sensitization and of overweight/obesity (and adiposopathy). In Aim 3, we will determine the role of IgE sensitization and of overweight/ obesity in the link between infant DNAm and asthma. Our pilot data lend compelling support to these hypotheses. In Aim 4, we will also integrate the available multi-omics data to further define the mechanisms that underlie DNAm signatures identified in Aims 1-3. We will replicate our findings in 963 children from a harmonized birth cohort – the Boston Birth Cohort. The R01 project will provide a unique opportunity to define the mechanisms linking IgE sensitization and overweight/obesity to incident asthma through investigating DNAm during infancy – a critical period of immune and lung development. The project will also provide a strong evidence base for developing targeted interventions for the primary prevention of childhood asthma.