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Genes, air pollution, and asthma severity in minority children

少数民族儿童的基因、空气污染和哮喘严重程度

基本信息

批准号：
9076396
负责人：
Esteban Gonzalez Burchard
金额：
$ 80.09万
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：
2016
资助国家：
美国
起止时间：
2016-04-22 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9076396
关键词：
Acute Address Affect African African American Air Air Pollution Asthma Caucasians Cells Child Clinical Data Death Rate Diagnosis Employee Strikes Environment Environmental Risk Factor Epithelial Cells Equation European Exposure to Frequencies Funding Gene Expression Genes Genetic Genetic Heterogeneity Genetic Risk Genetic Variation Genome Genomics Genotype Goals Health Policy In Vitro Individual Individual Differences Latino Lead Life Liquid substance Lung Lung diseases Measurement Measures Mediating Mexican Minority Modeling Morbidity - disease rate National Heart, Lung, and Blood Institute Native Americans Nose Particulate Matter Play Pollution Population Predisposition Public Health Puerto Rican Quantitative Trait Loci Race Recruitment Activity Respiratory physiology Risk Risk Factors Role Science Severities System Testing United States National Institutes of Health Variant base clinical practice ethnic difference gene environment interaction genetic risk factor genetic variant genome sequencing genome wide association study genome-wide improved minority children public health relevance racial and ethnic research study response risk variant social targeted treatment transcriptome transcriptome sequencing whole genome

项目摘要

DESCRIPTION (provided by applicant): Asthma affects 5% of the world population. In the U.S., asthma death rates are four-fold higher in Latinos and African Americans compared to Whites. Latinos and African Americans have varying degrees of African, European, and Native American genetic ancestry. This genetic heterogeneity has important clinical implications. In fact, we demonstrated that we can improve the diagnosis of lung disease among African Americans by as much as 15% by including genetic measures of ancestry into clinical lung function prediction equations (NEJM). We improved upon our results by incorporating sub-continental Native American ancestry into clinical lung function prediction equations for Latinos (Science). We also demonstrated that exposure to air pollution is associated with increased asthma risk among Latino and African American children, and that this increase in risk was greatest among African American children (AJRCCM). Subsequently, we demonstrated that environmental and social risk factors cannot fully explain the correlation between genetic ancestry and asthma severity and lung function (JACI). Clearly, we demonstrated that ancestry plays a strong role in determining normal clinical measures such as lung function and asthma severity. We hypothesize that gene- environment interactions contribute to population differences in lung function and asthma severity following exposure to air pollution. Racial/ethnic differences in the frequency and composition of genetic variation likely play an important role in asthma severity. To test this hypothesis we recruited the largest gene-environment study of asthma among minority children in the U.S. (N > 10,000). Our goal is to use integrative genomics to identify gene-by-air pollution interactions that influence lung function and asthma severity in minority children. We will leverage existing 1,600 whole genome sequences with air pollution-induced gene expression in nasal airway epithelial cells (NECs) from children with mild and severe asthma. We will integrate "individual-level" whole genome sequencing data with precise "cell-level" genetic and exposure-response experiments. We will identify genetic risk factors and gene-environment interactions that contribute to asthma severity, and determine cellular response mechanisms that mediate poor lung function and severe asthma using NECs exposed to air pollution.

描述（由申请人提供）：哮喘影响世界人口的 5%。在美国，拉丁裔和非裔美国人的哮喘死亡率是白人的四倍。拉丁裔和非裔美国人有不同程度的非洲、欧洲和美洲原住民的遗传血统。这种遗传异质性具有重要的临床意义。事实上，我们证明，通过将血统的遗传测量纳入临床肺功能预测方程 (NEJM)，我们可以将非裔美国人肺病的诊断率提高多达 15%。我们通过将次大陆美洲原住民血统纳入拉丁美洲人的临床肺功能预测方程中来改进我们的结果（科学）。我们还证明，接触空气污染与拉丁美洲和非裔美国儿童的哮喘风险增加有关，并且这种风险增加在非裔美国儿童中最为严重 (AJRCCM)。随后，我们证明环境和社会危险因素不能完全解释遗传血统与哮喘严重程度和肺功能（JACI）之间的相关性。显然，我们证明血统在确定正常临床指标（例如肺功能和哮喘严重程度）方面发挥着重要作用。我们假设基因-环境相互作用导致暴露于空气污染后肺功能和哮喘严重程度的人群差异。种族/民族遗传变异频率和组成的差异可能在哮喘严重程度中发挥重要作用。为了检验这一假设，我们招募了美国少数民族儿童中最大的哮喘基因环境研究（N > 10,000）。我们的目标是利用综合基因组学来识别影响少数民族儿童肺功能和哮喘严重程度的基因与空气污染之间的相互作用。我们将利用现有的 1,600 个全基因组序列，研究轻度和重度哮喘儿童的鼻气道上皮细胞 (NEC) 中空气污染诱导的基因表达。我们将把“个体水平”的全基因组测序数据与精确的“细胞水平”遗传和暴露反应实验相结合。我们将确定导致哮喘严重程度的遗传风险因素和基因-环境相互作用，并使用暴露于空气污染的 NEC 确定介导肺功能不良和严重哮喘的细胞反应机制。