Epigenomics of asthma risk factors and clinical subtypes in minority children

少数民族儿童哮喘危险因素及临床亚型的表观基因组学

基本信息

批准号：
10541199
负责人：
LUISA N BORRELL
金额：
$ 71.68万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541199
关键词：
Accounting Address Admixture Affect African American African American population Air Pollution Algorithms Allergic Disease American Asthma Biological Markers Biomedical Research Bronchodilator Agents Child Chronic Disease Clinical Clinical Research Collaborations Communities Complex Cytosine DNA Methylation DNA Sequence Data Data Set Disease Disparity Environment Environmental Epidemiology Environmental Risk Factor Epidemiology Epigenetic Process Ethnic Origin Ethnic Population Exposure to Extrinsic asthma Family history of Funding Genes Genetic Genomics Genotype Goals Guanine Heterogeneity Hispanic IgE Immune response Incidence Individual Intervention Latino Leukocytes Life Measures Mediating Mediation Methylation Mexican Mexican Americans Morbidity - disease rate Obesity Outcome Participant Pathway interactions Patient Selection Peripheral Pharmaceutical Preparations Phenotype Population Prevalence Puerto Rican RNA RNA Sequences Race Recording of previous events Research Respiratory Disease Respiratory Tract Infections Risk Risk Factors Science Serum Site Social Environment Spirometry Statistical Methods Testing Tobacco smoke United States Variant Work cell type clinical effect clinical epidemiology clinical risk clinical subtypes cohort diagnostic criteria disorder subtype eosinophil epigenetic marker epigenetic variation epigenomics ethnic disparity ethnic identity ethnic minority functional genomics genetic risk factor genome-wide genomic data health disparity high risk improved inorganic phosphate methylation pattern minority children mortality neutrophil novel power analysis profiles in patients programs racial disparity racial minority racial population response skin prick test social epidemiology social factors therapeutic target whole genome

项目摘要

PROJECT SUMMARY Asthma is the most common chronic disorder of children, with an estimated 300 million cases worldwide and with significant increases in incidence since the early 1980s. In the United States (U.S.), asthma prevalence, morbidity, mortality, and drug response vary substantially among racial and ethnic groups. While asthma was previously regarded as being a single clinical entity with a number of diagnostic criteria, it is now widely recognized that asthma represents multiple different pathobiological and clinical subtypes, which may underlie observed racial and ethnic variation. Furthermore, an individual's risk of developing asthma reflects a summation of genetic as well as various clinical risk factors. Importantly, clinical risk factors are not randomly distributed across racial and ethnic groups, and certain populations are more burdened than others. Our goal in this work is to identify cell types, genes, and pathways altered by exposure to clinical risk factors, thereby improving mechanistic understanding of asthma subtypes and elucidating the underlying networks by which these risk factors affect asthma disparities. To achieve this goal, we will determine the epigenetic profiles of patients with and without known asthma risk factors (Aim 1), identify common and unique epigenetic profiles associated with known and novel clinical asthma subtypes (Aim 2), and examine the contribution of common and unique epigenetic changes to the association of clinical risk factors with clinical asthma subtypes (Aim 3). We hypothesize that DNA methylation will provide the bridge that ties clinical risk factors with asthma disease subtypes and that this relationship may be modified by self-identified race/ethnicity and genetic ancestry thereby contributing to asthma disparities. Strong preliminary data from our group and others have shown that methylation, a long lasting but dynamic measure of cellular states, is highly correlated with exposure to clinical asthma risk factors, including early life respiratory infection, obesity, and maternal history of asthma. To execute this research program, we have assembled an interdisciplinary team with complementary expertise in epidemiology, clinical asthma, genetics, epigenetics, and statistical methods. Our team will study a unique cohort of minority children at the extremes of asthma prevalence and mortality (high risk Puerto Ricans and African Americans, and low risk Mexican Americans), who have existing demographic data, clinical exposures, genotypes, and RNA/DNA sequences. To our knowledge, there are no other groups within or outside the U.S. with populations as detailed as ours that are large enough to be well powered for these analyses. Therefore, we are the only group with the population needed and track record to successfully complete this project. Findings from our work will help: (i) provide the clinical and biomedical research communities with the largest methylation dataset on minority children produced to date, with a substantially increased value due to existing clinical, socio-environmental, and genetic data, (ii) improve risk profiling, especially for minority children, and (iii) precisely treat patients by selecting interventions using epigenetic markers accounting for clinical risk factors.

项目概要哮喘是儿童最常见的慢性疾病，全球估计有 3 亿例哮喘病例自 20 世纪 80 年代初以来发病率显着增加。在美国（U.S.），哮喘患病率不同种族和族裔群体的发病率、死亡率和药物反应差异很大。虽然哮喘是以前被认为是具有多种诊断标准的单一临床实体，现在它被广泛认识到哮喘代表多种不同的病理生物学和临床亚型，这可能是观察到种族和民族差异。此外，个人患哮喘的风险反映了一个总和遗传以及各种临床危险因素。重要的是，临床危险因素不是随机分布的跨种族和族裔群体，某些人群比其他人群负担更重。我们这项工作的目标是确定因暴露于临床风险因素而改变的细胞类型、基因和途径，从而提高对哮喘亚型的机制理解并通过以下方式阐明潜在的网络这些危险因素影响哮喘的差异。为了实现这一目标，我们将确定表观遗传图谱对具有和不具有已知哮喘危险因素的患者进行分析（目标 1），确定常见和独特的表观遗传特征与已知和新的临床哮喘亚型相关（目标 2），并检查常见哮喘亚型的贡献临床危险因素与临床哮喘亚型之间关联的独特表观遗传变化（目标 3）。我们假设 DNA 甲基化将提供将临床危险因素与哮喘联系起来的桥梁疾病亚型，并且这种关系可能会因自我认定的种族/民族和遗传血统而改变从而造成哮喘差异。我们小组和其他人的强有力的初步数据表明甲基化是一种持久但动态的细胞状态测量方法，与临床暴露高度相关。哮喘危险因素，包括生命早期呼吸道感染、肥胖和母亲哮喘病史。执行在这个研究项目中，我们组建了一个跨学科团队，在以下方面具有互补的专业知识流行病学、临床哮喘、遗传学、表观遗传学和统计方法。我们的团队将研究一个独特的群体少数族裔儿童的哮喘患病率和死亡率处于极端水平（高危波多黎各人和非洲人）美国人和低风险墨西哥裔美国人），他们拥有现有的人口统计数据、临床暴露、基因型和 RNA/DNA 序列。据我们所知，美国境内或境外没有其他组织。像我们这样详细的人口数量足够大，足以进行这些分析。因此，我们是唯一拥有成功完成该项目所需人口和记录的团体。我们的工作结果将有助于：(i) 为临床和生物医学研究界提供最大的迄今为止制作的少数民族儿童甲基化数据集，由于现有的临床、社会环境和遗传数据，(ii) 改善风险分析，尤其是少数群体儿童，以及 (iii) 通过使用考虑临床危险因素的表观遗传标记选择干预措施来精确治疗患者。