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

项目总结 为儿童哮喘制定初级预防策略的主要挑战是早期 确定可修改的危险因素(如表观基因组、免疫球蛋白E敏感性、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 婴儿期甲基化(DNaM)在发育过程中有三个结果：IgE敏化， 超重/肥胖(和脂肪病)，并最终在两个互补的多中心前瞻性研究中出现哮喘 队列研究。第35次多中心呼吸道研究合作(MARC-35)研究(U01AI087881)是一项 正在进行的对921名因毛细支气管炎住院的婴儿进行的17中心队列研究--毛细支气管炎的高危人群 哮喘。另一项正在进行的队列研究MARC-43(UG3/UH3OD023253)包括600名健康婴儿。这些 种族/民族多样化的队列(52%的非裔美国人或西班牙裔)真正具有互补性， 接受类似程序(例如，特定的IgE和细胞因子测量)的年龄相近的参与者 (例如，婴儿期、3岁和6岁)。随访包括一年两次的访谈和6岁以上的医疗记录 几年，到目前为止有大约90%的随访率。参与者在6岁时接受面对面检查 哮喘的表型。目前的R01项目将通过分析来扩展这些大型的、特征良好的队列 对1,521名婴儿进行全血基因组dNaM检测，并探讨其与婴幼儿先天性心脏病发生的关系。 三种主要结果：免疫球蛋白增敏、超重/肥胖和哮喘。在目标1中，我们将确定 婴儿血液dNaM特征与发生哮喘风险的关系，包括其表型。我们 还将调查这些dNaM从婴儿期到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特征与发病风险的关系。 免疫球蛋白增敏和超重/肥胖(和脂肪病)。在目标3中，我们将确定IgE的作用 在婴儿dNaM和哮喘之间的联系中，对超重/肥胖的敏感性。我们的试点数据出借给 对这些假说的有力支持。在AIM 4中，我们还将整合现有的多组学数据以 进一步定义目标1-3中确定的dNaM签名所依据的机制。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 一个独特的机会来确定IgE敏化和超重/肥胖与事件相关的机制 通过研究婴儿期-免疫和肺发育的关键时期-dNaM来研究哮喘。这个 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 儿童哮喘的症状。

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.