Genetic Susceptibility to Asthma and IndoorAir Pollution in Peru

描述(申请人提供)：哮喘是一种流行病，对儿童、穷人和某些种族/民族群体有不成比例的影响。拉美裔/拉美裔是美国增长最快的少数族裔人口，受哮喘发病率的影响不成比例。从1990年到2000年，在美国人口普查调查中，将自己的种族标记为秘鲁人的人数增加了81%，秘鲁的哮喘患病率是世界上最高的之一。哮喘是一种复杂的疾病，哮喘的遗传风险和哮喘发病率可能会因环境暴露而改变。室内环境尤其令人担忧，因为大多数人大部分时间都是在室内度过的。这项应用的研究人员已经证明，室内暴露的高水平，包括颗粒物(PM)和二氧化氮(NO2)，独立地与更高的哮喘发病率相关，并且在秘鲁家庭中尤其高。由于国内PM和NO2浓度的差异，哮喘的负担是巨大的；然而，并不是所有的儿童都容易受到污染物暴露的影响，个人之间的反应存在很大差异。这些发现表明，在哮喘的发生发展过程中，遗传易感性和环境暴露之间存在很大的相互作用。为了解决遗传易感性对室内空气污染对哮喘不利影响的关键问题，我们将在秘鲁的基础设施和正在进行的数据收集工作的基础上再接再厉。我们提出了一项候选基因研究，以确定秘鲁利马和汤布斯两个城市与哮喘及其相关特征(即哮喘严重程度、肺功能、呼吸道炎症)相关的基因变异与室内空气污染物暴露的关系。我们将优先考虑已发表的哮喘全基因组关联研究确定的候选基因，以及那些被认为与污染物暴露和哮喘有关的氧化应激途径中的候选基因。我们将在来自秘鲁利马(n=1400)的哮喘病例和对照中确定的关联进行交叉验证，在从秘鲁Tumbe招募的哮喘病例和对照(n=400)的第二独立人群中进行交叉验证。具体目标1：确定秘鲁儿童哮喘的相关基因。具体目标2：确定哮喘的遗传风险是否受室内空气污染物(PM、NO2)浓度的影响。我们预计将确定哮喘的候选基因和与普通人群相关的相关特征，以及那些导致秘鲁个人哮喘发病率差异的基因。确定人口中特别容易受到空气污染影响的亚群是一个重要的目标，因为结果可以用来确定最有可能从避免接触中受益的人。 公共卫生相关性：哮喘是儿童中最常见的慢性病，全世界有超过3亿人患有哮喘，这表明公共卫生负担很大。我们预计将确定哮喘的候选基因和与普通人群相关的相关特征，以及那些导致秘鲁个人哮喘发病率差异的基因。确定人口中特别容易受到空气污染影响的亚群是一个重要的目标，因为结果可以用来确定最有可能从避免接触中受益的人。

DESCRIPTION (provided by applicant): Asthma is an epidemic that disproportionately affects children, the poor and certain racial/ethnic groups. Latinos/Hispanics are the fastest growing minority population in the US and are disproportionately affected by asthma morbidity. From 1990 to 2000 there was an 81 percent increase in number of people that mark their ethnic origin as Peruvian on the US Census survey and the prevalence of asthma in Peru is among one of the highest in the world. Asthma is a complex disease and genetic risk for asthma and asthma morbidity may be modified by environmental exposures. The indoor environment is of particular concern as most people spend the majority of their time indoors. Investigators in this application have shown that high levels of indoor exposures, including particulate matter (PM) and nitrogen dioxide (NO2), are independently associated with greater asthma morbidity, and are particularly high in Peruvian homes. The burden of asthma attributable to differences in domestic PM and NO2 concentrations is substantial; however, not all children are susceptible to effects of pollutant exposure and a large variation in response exists between individuals. These findings suggest a strong possibility of an interaction between genetic predisposition and environmental exposure in the development of asthma. To address the critical questions of the role of genetic susceptibility to the adverse effects of indoor air pollution on asthma, we will build upon the infrastructure and ongoing data collection efforts in Peru. We propose a candidate gene study to identify genetic variants associated with asthma and its associated traits (i.e., asthma severity, pulmonary function, airway inflammation) in relation to indoor air pollutant exposure in two Peruvian cities, Lima and Tumbes. We will prioritize candidate genes identified by published genome-wide association studies for asthma as well as those in the oxidative stress pathway thought to be relevant to pollutant exposure and asthma. We will cross-validate associations identified in well characterized asthma cases and controls from Lima, Peru (n=1,400), in a second independent population of asthmatic cases and controls recruited from Tumbes, Peru (n=400). Specific Aim #1: To identify genes associated with asthma in children in Peru. Specific Aim #2: To determine if genetic risk for asthma is modified by indoor air pollutant (PM, NO2) concentrations. We anticipate identifying candidate genes for asthma and associated traits relevant to both the general population as well as those contributing to disparities in asthma morbidity among individuals in Peru. Identifying subgroups of the population who are particularly vulnerable to air pollution is an important objective, as the results can be used to identify people most likely to benefit from exposure avoidance. PUBLIC HEALTH RELEVANCE: Asthma is the most common chronic disease in children and over 300 million people suffer from asthma worldwide, suggesting a large public health burden. We anticipate identifying candidate genes for asthma and associated traits relevant to both the general population as well as those contributing to disparities in asthma morbidity among individuals in Peru. Identifying subgroups of the population who are particularly vulnerable to air pollution is an important objective, as the results can be used to identify people most likely to benefit from exposure avoidance.