Methylomic and metabolomic determinants of Lung Function in Asthmatics

哮喘患者肺功能的甲基组学和代谢组学决定因素

• 批准号: 10592399
• 负责人: Priyadarshini Kachroo
• 金额: $ 17.28万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592399
• 关键词: Address; Adolescence; Advisory Committees; Affect; Amino Acids; Area; Asthma; Automobile Driving; Award; Bioinformatics; Biological Markers; Cell Survival; Child; Childhood; Childhood Asthma; Clinical; Communication; Complement; Complex; Costa Rica; DNA Integration; DNA Methylation; Data; Data Scientist; Data Set; Development Plans; Diagnosis; Disease; Doctor of Philosophy; Ensure; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Ethics; Future; Genes; Genetic; Genetic Risk; Genetic Variation; Genome; Goals; Grant; Growth; Heritability; Hospitals; Impairment; Individual; Intervention; Joints; Life; Life Cycle Stages; Link; Lung; Maps; Measures; Mediating; Mediation; Medicine; Mentors; Mentorship; Metabolic Pathway; Metabolism; Methodology; Methods; Methylation; Molecular; Multiomic Data; Network-based; Obstructive Lung Diseases; Outcome; Pathogenesis; Pathway interactions; Phase; Phenotype; Play; Positioning Attribute; Public Health; Pulmonary Function Test/Forced Expiratory Volume 1; Quantitative Trait Loci; Regulator Genes; Research; Research Design; Research Personnel; Risk; Role; Sphingolipids; Sum; Testing; Training; Training Support; Trans-Omics for Precision Medicine; Vitamin D; Whole Blood; Woman; antenatal; asthmatic; biomarker driven; career; career development; clinical phenotype; clinical training; clinical translation; cohort; disease phenotype; genetic epidemiology; genetic variant; genome sequencing; genome-wide; genome-wide analysis; innovation; insight; integration site; lung development; medical schools; metabolome; metabolomics; methylome; methylomics; multiple omics; potential biomarker; programs; prospective; pulmonary function; research and development; risk prediction; risk variant; skills; success; whole genome

PROJECT SUMMARY/ABSTRACT Asthma progression is associated with reduced growth and an increased decline in lung function (LF) that is thought to arise from a complex interplay of genes and environment. While several asthma genetic risk loci have been identified to-date, an in-depth utilization of how environmental factors interact with these loci remains limited. The methylome and the metabolome are both heavily influenced by the environment and recent studies confirm a link between both omes. Integrating DNA methylation with the metabolome could be a powerful approach to obtain converging evidence of specific pathways influencing asthmatic lung function trajectories at the genome-wide level. While previous studies have investigated the role of the metabolome or methylome with regard to lung function, none have investigated both “omes” simultaneously for lung function outcomes in asthmatics. The central hypothesis of this proposal is that DNA methylation (CpG sites) plays a critical role in modulating downstream metabolites and thus metabolic pathways, some of which may be driven by an underlying genetic effect on lung function in children with asthma. We want to specifically investigate multi-omic data from Wnt, Hippo and sphingolipid pathways, known to affect asthmatic lung function generally and in our preliminary data. We capitalize on the genetic, methylomic and metabolomic data generated from three large prospective childhood cohorts including two from the Trans-omics for Precision Medicine (TOPMed) consortium: Childhood Asthma Management Program (CAMP) and The Genetic Epidemiology of Asthma in Costa Rica (GECRA) study and an independent cohort: The Vitamin D Antenatal Asthma Reduction Trial (VDAART). This study seeks to integrate multiple omics using innovative and state-of-the-art methodologies: quantitative trait loci (QTL) mapping to identify genome-methylome associations with LF (Aim 1), QTL mapping and causal inference testing to evaluate methylome-metabolome associations with LF (Aim 2), correlation-based network methods to identify a highly correlated set of omic-driven biomarkers in dysregulated pathways (Aim 3). Priyadarshini Kachroo, PhD, MS is a bioinformatician whose long-term career goal is to transition towards becoming an independent data scientist with expertise in utilizing multi-omic approaches to complex disease phenotypes. As Dr. Kachroo completes these aims, her career development plan will support her training goals: 1) deepen clinical understanding of asthmatic LF phenotypes; 2) expand on the statistical skills including causal inference testing 3) develop skill-set of network methods for integrating multi-omic datasets 4) enhance skills in study-design, mentorship and the ethics of scientific conduct and communication of research. Dr. Kachroo’s strong quantitative and methodological background well position her to accomplish these goals, complete the aims of this proposal and prepare her for an independent research career. The support of a diverse and world- class mentoring and advisory team in the Channing Division of Network Medicine at Brigham and Women’s Hospital and Harvard Medical School complement the research areas and ensure success of this proposal.

项目摘要/摘要 哮喘进展与生长降低和肺功能下降（LF）有关 被认为是由基因和环境的复杂相互作用引起的。而几个哮喘遗传风险基因座有 已确定至今，对环境因素如何与这些基因座相互作用的深入利用仍然存在 有限的。甲基组和代谢组都受环境和最近的研究的影响很大 确认两个OME之间的联系。将DNA甲基化与代谢组相结合可能是强大的 获得影响哮喘肺功能轨迹的特定途径的收敛证据的方法 全基因组水平。虽然先前的研究调查了代谢组或甲基甲基的作用 关于肺功能，没有一个仅针对肺功能结果研究了两个“ eme” 哮喘患者。该提案的中心假设是DNA甲基化（CpG位点）扮演着关键 在调节下游代谢产物和代谢途径中的作用，其中一些可以驱动 通过对哮喘儿童肺功能的潜在遗传作用。我们想专门研究 来自Wnt，河马和鞘脂途径的多摩变数据，已知会影响哮喘肺功能 在我们的初步数据中。我们利用由 三个大型的前瞻性童年队列，包括跨词的两名精密医学（顶部） 财团：儿童哮喘管理计划（CAMP）和哮喘的遗传流行病学 哥斯达黎加（GECRA）研究和一项独立队列：维生素D产前减少哮喘试验 （vdaart）。这项研究旨在使用创新和最先进的方法整合多个OMIC： 定量性状基因座（QTL）映射以识别与LF（AIM 1），QTL映射的基因组 - 甲基团关联 和因果推理测试，以评估与LF（AIM 2），基于相关的甲基化体 - 代谢组关联 网络方法可以识别失调途径中高度相关的OMIC驱动生物标志物集（AIM 3）。 Priyadarshini Kachroo，博士，MS是一位生物信息学家，其长期职业目标是过渡到 成为具有使用多词方法的复杂疾病的独立数据科学家 表型。当Kachroo博士完成这些目标时，她的职业发展计划将支持她的培训目标： 1）加深对哮喘LF表型的临床理解； 2）扩展包括催化剂在内的统计技能 推理测试3）开发用于集成多摩尼克数据集的网络方法的技能集4）提高技能 研究设计，心态和科学行为和研究的伦理。 Kachroo博士 强有力的定量和方法论背景很好地定位她来实现这些目标，完成 该提案的目的是为她准备独立的研究职业。多元化和世界的支持 Brigham和妇女网络医学的Channing部门的班级指导和咨询团队 医院和哈佛医学院完成了研究领域，并确保该提案的成功。