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

婴儿血液表观基因组和 IgE 致敏、肥胖和哮喘的风险：MARC-35/43 队列

• 批准号: 10684901
• 负责人: Kohei Hasegawa
• 金额: $ 62.91万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-13 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684901
• 关键词: 3 year old; 6 year old; Adult; Affect; African American; Age; American; Asthma; Birth; Blood; Blood specimen; Boston; Bronchiolitis; Bronchodilator Agents; CCL7 gene; Child; Childhood; Childhood Asthma; Cohort Studies; Collaborations; DNA Methylation; Data; Development; Disease Outcome; Early identification; Enrollment; Epigenetic Process; Extrinsic asthma; Foundations; Funding; Genetic; Heterogeneity; Hispanic; Hospitalization; Hypersensitivity; IgE; Immune; Immunologics; Infant; Inflammation; Intervention; Interview; Link; Literature; Measurement; Mediating; Mediator; Medical Records; Metabolism; Multiomic Data; NF-kappa B; National Institute of Allergy and Infectious Disease; Not Hispanic or Latino; Obesity; Outcome; Overweight; Parents; Participant; Pathway interactions; Persons; Phenotype; Play; Population; Positioning Attribute; Prevalence; Prevention strategy; Primary Prevention; Procedures; Prospective, cohort study; Public Health; Race; Reporting; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Sphingolipids; Strategic Planning; Testing; United States National Institutes of Health; Variant; Work; clinical phenotype; cohort; cost effectiveness; critical period; cytokine; epigenome; epigenomics; ethnic diversity; evidence base; follow-up; genome wide association study; genome wide methylation; genome-wide; genomic locus; high risk; high risk population; infancy; innovation; lung development; metabolomics; microbiome research; modifiable risk; novel; novel strategies; obesity-associated asthma; peripheral blood; racial diversity; success; transcriptomics

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.

项目概要 制定儿童哮喘一级预防策略的主要挑战是早期预防 识别可改变的危险因素（例如表观基因组、IgE 致敏、超重/肥胖）和 该 R01 项目的首要目标是研究血液 DNA 的作用。 婴儿期甲基化 (DNAm) 会产生三种结果：IgE 致敏、 两个互补的多中心前瞻性研究中的超重/肥胖（和脂肪病），以及最终的哮喘 第 35 次多中心气道研究合作 (MARC-35) 研究 (U01AI087881) 是一项队列研究。 正在进行的 17 中心队列研究，纳入了 921 名因细支气管炎住院的婴儿——这是罹患细支气管炎的高危人群 另一项正在进行的队列研究 MARC-43 (UG3/UH3 OD023253) 包括 600 名健康婴儿。 种族/族裔多样化群体（52% 非裔美国人或西班牙裔）确实是互补的， 参与者在相似的年龄接受相似的程序（例如特定 IgE 和细胞因子测量） （例如，婴儿期、3 岁和 6 岁）。随访包括每年两次的访谈和 6 岁以上的医疗记录。 年，迄今为止约有 90% 的参与者在 6 岁时接受了现场检查。 目前的 R01 项目将通过分析来扩展这些大型的特征明确的队列。 1,521 名婴儿的血液全基因组 DNAm，然后检查它们与发育的关系 三个主要结果：IgE 致敏、超重/肥胖和哮喘 在目标 1 中，我们将确定以下因素： 婴儿血液 DNAm 特征与罹患哮喘的风险（包括其表型）之间的关联。 还将研究这些 DNAm 从婴儿期到 3 岁的纵向变化，以及它们与 在目标 2 中，我们将检查婴儿血液 DNAm 特征与罹患哮喘风险的关系。 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。 我们的试点数据提供了婴儿 DNAm 与哮喘之间联系的敏感性和超重/肥胖。 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 特征背后的机制，我们将复制我们的目标。 R01 项目将提供来自协调出生队列（波士顿出生队列）的 963 名儿童的研究结果。 定义将 IgE 致敏和超重/肥胖与事件联系起来的机制的独特机会 通过在婴儿期（免疫和肺部发育的关键时期）研究 DNAm 来研究哮喘。 项目还将为制定初级预防有针对性的干预措施提供强有力的证据基础 儿童哮喘。

项目成果

Integrated-omics endotyping of infants with rhinovirus bronchiolitis and risk of childhood asthma.

患有鼻病毒细支气管炎的婴儿的综合组学内分型和儿童哮喘的风险。

• 发表时间: 2021
• 作者: Raita, Yoshihiko;Camargo Jr, Carlos A;Bochkov, Yury A;Celedón, Juan C;Gern, James E;Mansbach, Jonathan M;Rhee, Eugene P;Freishtat, Robert J;Hasegawa, Kohei
• 通讯作者: Hasegawa, Kohei

metabolomicsR: a streamlined workflow to analyze metabolomic data in R.

metabolomicsR：在 R 中分析代谢组数据的简化工作流程。

• 发表时间: 2022
• 作者: Han, Xikun;Liang, Liming
• 通讯作者: Liang, Liming

Nasal airway microRNA profiling of infants with severe bronchiolitis and risk of childhood asthma: a multicentre prospective study.

患有严重细支气管炎和儿童哮喘风险的婴儿的鼻气道 microRNA 分析：一项多中心前瞻性研究。

• 发表时间: 2023-08
• 作者: Zhu, Zhaozhong;Freishtat, Robert J;Harmon, Brennan;Hahn, Andrea;Teach, Stephen J;Pérez;Hasegawa, Kohei;Camargo Jr, Carlos A;MARC
• 通讯作者: MARC

Association of Growth Trajectory Profiles with Asthma Development in Infants Hospitalized with Bronchiolitis.

因毛细支气管炎住院的婴儿生长轨迹与哮喘发展的关联。

• 发表时间: 2022-03
• 作者: Nanishi, Makiko;Fujiogi, Michimasa;Stevenson, Michelle;Liang, Liming;Qi, Ying Shelly;Raita, Yoshihiko;Hasegawa, Kohei;Camargo Jr, Carlos A
• 通讯作者: Camargo Jr, Carlos A

Association of Nasopharyngeal and Serum Glutathione Metabolism with Bronchiolitis Severity and Asthma Risk: A Prospective Multicenter Cohort Study.

鼻咽和血清谷胱甘肽代谢与细支气管炎严重程度和哮喘风险的关联：一项前瞻性多中心队列研究。

• 发表时间: 2022-07-22
• 影响因子: 4.1
• 作者: Kyo, Michihito;Zhu, Zhaozhong;Nanishi, Makiko;Shibata, Ryohei;Ooka, Tadao;Freishtat, Robert J;Mansbach, Jonathan M;Camargo Jr, Carlos A;Hasegawa, Kohei
• 通讯作者: Hasegawa, Kohei