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

• 批准号: 10323032
• 负责人: LUISA N BORRELL
• 金额: $ 71.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10323032
• 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; Communities; Complex; Cytosine; DNA Methylation; DNA Sequence; Data; Data Set; Disease; Environment; Environmental Epidemiology; Environmental Risk Factor; Epidemiology; Epigenetic Process; Ethnic Origin; Ethnic group; Exposure to; Extrinsic asthma; Family history of; Fibrinogen; Funding; Genes; Genetic; Genetic Risk; 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; Patients; 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 phenotype; clinical risk; clinical subtypes; cohort; diagnostic criteria; disorder subtype; eosinophil; epigenetic marker; epigenetic variation; epigenomics; ethnic identity; ethnic minority; functional genomics; 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 and ethnic; racial and ethnic disparities; response; skin prick test; social epidemiology; social factors; therapeutic target; whole genome

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.

项目总结 哮喘是儿童最常见的慢性疾病，全世界估计有3亿病例， 自20世纪80年代初以来发病率显著上升。在美国，哮喘患病率， 不同种族和民族的发病率、死亡率和药物反应有很大差异。而哮喘则是 以前被认为是具有多个诊断标准的单一临床实体，现在被广泛 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，一个人患哮喘的风险反映了一个总结 遗传因素以及各种临床风险因素。重要的是，临床风险因素不是随机分布的。 在种族和民族群体中，某些人群的负担比其他人群更重。 我们在这项工作中的目标是识别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 这些危险因素会影响哮喘的差异。为了实现这一目标，我们将确定表观遗传学特征 对有和没有已知哮喘危险因素的患者(目标1)，确定共同和独特的表观遗传学特征 与已知和新的临床哮喘亚型相关(目标2)，并检查共同的 以及临床危险因素与临床哮喘亚型之间关系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，这种关系可能会被自我确认的种族/民族和遗传血统所改变 从而导致了哮喘的差异。来自我们小组和其他人的强劲的初步数据表明， 甲基化是对细胞状态的长期而动态的测量，与临床暴露高度相关。 哮喘危险因素，包括早年呼吸道感染、肥胖和母亲哮喘史。执行，执行 在这项研究计划中，我们组建了一个跨学科的团队，在 流行病学、临床哮喘、遗传学、表观遗传学和统计学方法。我们的团队将研究一个独特的队列 少数族裔儿童处于哮喘患病率和死亡率的极端水平(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)，他们有现有的人口统计数据、临床暴露、 基因类型和RNA/DNA序列。据我们所知，在美国国内外没有其他组织。 与我们一样详细的人口数量足以为这些分析提供充足的动力。因此，我们 是唯一拥有成功完成这一项目所需人口和记录的群体。 我们的工作成果将有助于：(I)为临床和生物医学研究社区提供最大的 迄今为止产生的少数族裔儿童的甲基化数据集，由于现有的 临床、社会环境和遗传数据；(2)改善风险概况，特别是针对少数族裔儿童；和(3) 通过使用考虑临床风险因素的表观遗传标记物选择干预措施来精确治疗患者。