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: 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
• 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

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.

项目摘要 哮喘是儿童最常见的慢性疾病，全世界估计有3亿例， 自20世纪80年代初以来，发病率显著增加。在美国（U.S.），哮喘患病率， 发病率、死亡率和药物反应在种族和族裔群体之间差异很大。虽然哮喘是 以前被认为是一个单一的临床实体，有许多诊断标准，现在被广泛 认识到哮喘代表了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 遗传和各种临床风险因素。重要的是，临床风险因素不是随机分布的 在不同种族和族裔群体中，某些群体的负担比其他群体更重。 我们在这项工作中的目标是确定细胞类型，基因和途径改变暴露于临床风险因素， 从而提高对哮喘亚型的机制理解，并阐明潜在的网络， 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概况， 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特征 与已知和新的临床哮喘亚型相关（目的2），并检查常见的 和独特的表观遗传学变化与临床哮喘亚型的临床危险因素的关联（目的3）。 我们假设DNA甲基化将为哮喘的临床危险因素提供联系的桥梁 疾病亚型，这种关系可能会被自我确定的种族/民族和遗传祖先改变 从而导致哮喘差异。来自我们小组和其他人的有力的初步数据表明， 甲基化是细胞状态的一种持久但动态的量度，与临床暴露高度相关。 哮喘危险因素，包括早期呼吸道感染、肥胖和母亲哮喘史。执行 这项研究计划，我们已经组建了一个跨学科的团队，具有互补的专业知识， 流行病学、临床哮喘、遗传学、表观遗传学和统计学方法。我们的团队将研究一个独特的群体 少数民族儿童的哮喘患病率和死亡率处于极端（高风险的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学数据，临床暴露， 基因型和RNA/DNA序列。据我们所知，在美国境内外没有其他组织。 像我们这样详细的人群足够大，可以很好地进行这些分析。所以我们 是唯一一个拥有所需人口和成功完成该项目的记录的群体。 我们的工作结果将有助于：（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）改进风险分析，特别是针对少数民族儿童的风险分析，以及（iii） 通过使用表观遗传标记选择干预措施来精确治疗患者，以解释临床风险因素。