Genes, air pollution, and asthma severity in minority children

 描述（由申请人提供）：哮喘影响世界人口的5%。在美国，与白人相比，拉丁美洲人和非洲裔美国人的哮喘死亡率高出四倍。拉丁美洲人和非洲裔美国人有不同程度的非洲，欧洲和美洲原住民遗传祖先。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肺部疾病的诊断提高15%。我们通过将亚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来改进我们的结果（科学）。我们还证明了暴露于空气污染与拉丁美洲和非洲裔美国儿童哮喘风险增加有关，并且这种风险增加在非洲裔美国儿童中最大（AJRCCM）。随后，我们证明了环境和社会风险因素不能完全解释遗传血统与哮喘严重程度和肺功能之间的相关性。显然，我们证明了祖先在确定正常的临床指标如肺功能和哮喘严重程度方面起着重要作用。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/族裔 遗传变异的频率和组成的差异可能在哮喘的严重程度中起重要作用。为了验证这一假设，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）。我们的目标是利用整合基因组学来确定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气道上皮细胞（NEC）中进行空气污染诱导的基因表达。我们将整合“个人水平”的全基因组测序数据与精确的“细胞水平”的遗传和免疫应答实验。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，并确定使用暴露于空气污染的NEC介导肺功能不良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.