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.

项目摘要哮喘是最常见的儿童慢性疾病，估计有3亿例病例自1980年代初以来的发病率显着增加。在美国（美国），哮喘患病率，在种族和族裔中，发病率，死亡率和药物反应差异很大。而哮喘是以前被认为是具有许多诊断标准的单个临床实体，现在已广泛认识到哮喘代表多种不同的病理生物学和临床亚型，这可能是观察到的种族和种族差异。此外，个人患哮喘的风险反映了一个总结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种族和种族中，以及某些人口的负担比其他人负担更大。我们在这项工作中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理理解，并通过这些风险因素会影响哮喘差异。为了实现这一目标，我们将确定表观遗传特征有或没有已知哮喘危险因素的患者（AIM 1），确定常见和独特的表观遗传特征与已知和新颖的临床哮喘亚型相关（AIM 2），并检查常见的贡献以及临床危险因素与临床哮喘亚型的关联的独特表观遗传学变化（AIM 3）。我们假设DNA甲基化将提供将临床风险因素与哮喘联系起来的桥梁疾病亚型，这种关系可以通过自我认同的种族/种族和遗传血统来改变从而导致哮喘差异。来自我们小组和其他人的强大初步数据表明甲基化是一种持久但动态的细胞状态度量，与暴露于临床高度相关哮喘危险因素，包括早期呼吸道感染，肥胖和哮喘的产妇史。执行该研究计划，我们组建了一个具有互补专业知识的跨学科团队流行病学，临床哮喘，遗传学，表观遗传学和统计方法。我们的团队将学习独特的队列哮喘患病率和死亡率极端的少数民族儿童（高风险波多黎各人和非洲人美国人和低风险的墨西哥裔美国人），有人口统计数据，临床暴露，基因型和RNA/DNA序列。据我们所知，美国没有其他团体人口与我们的人群一样详细，足以容纳这些分析。因此，我们是唯一拥有人口所需的群体，也是成功完成该项目的记录。我们工作的发现将有所帮助：（i）为临床和生物医学研究社区提供最大的临床和生物医学研究社区迄今为止生产的少数族裔儿童的甲基化数据集，由于现有临床，社会环境和遗传数据，（ii）改善风险分析，尤其是少数民族儿童，以及（iii）通过使用表观遗传标志物选择临床危险因素的表观遗传标记来精确治疗患者。