Genes, air pollution, and asthma severity in minority children

 描述(申请人提供)：哮喘患者占世界人口的5%。在美国，拉美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人、欧洲人和美洲原住民的遗传祖先。这种遗传异质性具有重要的临床意义。事实上，我们证明，通过将祖先的遗传指标纳入临床肺功能预测方程(NEJM)，我们可以将非裔美国人的肺部疾病诊断提高高达15%。我们通过将次大陆美洲原住民血统纳入拉丁裔临床肺功能预测方程(《科学》)，对我们的结果进行了改进。我们还证明，暴露在空气污染中与拉美裔和非裔美国儿童哮喘风险增加有关，而且这种风险增加在非裔美国儿童中最大(AJRCCM)。随后，我们证明了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，我们证明了血统在决定肺功能和哮喘严重程度等正常临床指标方面发挥着重要作用。我们假设，在暴露于空气污染后，基因与环境的相互作用导致了肺功能和哮喘严重程度的人群差异。种族/民族 基因变异的频率和组成的差异可能对哮喘的严重程度起到重要作用。为了验证这一假设，我们招募了美国最大的关于少数族裔儿童哮喘的基因环境研究(N&GT；10,000)。我们的目标是使用整合基因组学来确定影响少数族裔儿童肺功能和哮喘严重程度的基因与空气污染的相互作用。我们将利用现有的1,600个全基因组序列，在轻度和重度哮喘儿童的鼻呼吸道上皮细胞(NEC)中进行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。我们将识别导致哮喘严重程度的遗传危险因素和基因-环境相互作用，并利用暴露于空气污染中的NECS确定介导肺功能低下和严重哮喘的细胞反应机制。

 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.