Diesel, Allergens and Gene Interaction and Child Atopy

描述（由研究者提供）：这一竞争性修订将严格遵守ARRA，保留研究助理的职位，为研究助理和本科生创造一个兼职职位，并通过购买美国大型公司的基因分型服务来刺激经济。这一修订也有助于创建新的研究目标，探索父母资助范围之外的尼古丁代谢和氧化应激遗传学的关联，并将在不到一年的时间内完成。接触碳排放污染物是儿童呼吸系统疾病的一个主要因素。尼古丁和可替宁的测量代表了ETS中存在的超过4700种化学物质的全身暴露，其中许多具有促炎特性，包括尼古丁。ETS还诱导活性氧（ROS）的产生和氧化应激，这些活性氧主要被谷胱甘肽- s -转移酶（GST）家族中的酶灭活。在与尼古丁代谢和氧化应激相关的基因中发现了功能多态性，这些基因可以减少可替宁的形成（从而增加尼古丁），并使活性氧失活。核心假设是，尼古丁代谢和/或氧化应激相关基因变异等位基因的携带者可能会增加全身尼古丁，从而导致ETS生物标志物的错误分类，并增加包括哮喘在内的呼吸系统疾病的患病率和加重。我们将验证这一假设，目的如下：1)确定尼古丁代谢基因变异等位基因对尼古丁和可替宁生物标志物的影响。我们假设尼古丁代谢途径中多个基因的变异等位基因会导致全身尼古丁增加和可替宁形成减少，从而导致ETS生物标志物的错误分类。2)研究尼古丁代谢和氧化应激相关基因与呼吸结局的关系。我们假设，携带尼古丁代谢和/或氧化应激相关基因变异等位基因的儿童会增加呼吸系统疾病的患病率和恶化程度。这一竞争性修订将评估参与CCAAPS的受试者，CCAAPS是一个具有过敏性疾病发展高风险特征的出生队列，其主要目的是确定柴油尾气对儿童过敏性疾病和哮喘的影响。目前，父母队列正在收集7岁儿童的呼吸系统疾病（包括哮喘）以及DNA、头发样本和ETS暴露的父母报告。本修订版建议对头发样本中的尼古丁代谢和氧化应激相关基因进行功能和标记单核苷酸多态性（snp）的基因分型，并定量尼古丁和可替宁。提出的这项研究意义重大，因为它将提供新的信息，说明在流行病学研究中将尼古丁和可替宁作为ETS暴露的生物标志物进行量化时，需要考虑基因组成。此外，这项研究可能为未来治疗方法的发展提供基础，以确定遗传上易患呼吸系统疾病的儿童。

DESCRIPTION (provided by investigator): This competitive revision will stringently adhere to the ARRA by retaining the position of a Research Associate and creating one position for a Research Assistant and a part-time position for an undergraduate student and stimulating the economy through the purchase of genotyping services from a large US-based company. This revision also serves to create new research objectives to explore the associations of nicotine metabolism and oxidative stress genetics outside of the scope of the parent grant, and will be completed in less than one year. ETS exposure is a major contributor to childhood respiratory disorders. Nicotine and cotinine measures serve as a proxy for systemic exposure to over 4700 chemicals present in ETS, many with pro-inflammatory properties, including nicotine. ETS also induces the production of reactive oxygen species (ROS) and oxidative stress, which are deactivated primarily by enzymes in the glutathione-S-transferase (GST) family. Functional polymorphisms have been identified in genes related to nicotine metabolism and oxidative stress that can decrease cotinine formation (and therefore increased nicotine), and deactivation of ROS. The central hypothesis is that carriers of variant alleles in nicotine metabolism and/or oxidative stress related genes may have increased systemic nicotine, and therefore misclassification of ETS biomarkers, and increased prevalence and exacerbation of respiratory disorders, including asthma. We will test this hypothesis with the following aims: 1) Determine the effects of variant alleles in nicotine metabolism genes on biomarkers of nicotine and cotinine. We hypothesize that variant alleles in multiple genes along the nicotine metabolism pathway will cause increased systemic nicotine and decreased cotinine formation, leading to misclassification of ETS biomarkers. 2) Examine the associations of nicotine metabolism and oxidative stress related genes on respiratory outcomes. We hypothesize that children with variant alleles in nicotine metabolizing and/or oxidative stress related genes will have increased prevalence and exacerbation of respiratory disorders. This competitive revision will evaluate subjects participating CCAAPS, a well-characterized birth cohort at high-risk for development of allergic disease, whose main objective is to determine the effects of diesel exhaust on childhood allergic disease and asthma. Objective measures of respiratory disease, including asthma, as well as DNA, hair samples and parental report of ETS exposures are currently being collected from the children aged seven by the parent cohort. This revision proposes to genotype nicotine metabolism and oxidative stress related genes for both functional and tagging single nucleotide polymorphisms (SNPs), as well as quantify nicotine and cotinine in hair samples. The research proposed is significant because it will provide novel information on the need to consider genetic make-up when quantifying nicotine and cotinine as biomarkers of ETS exposure in epidemiologic studies. Further, this research may provide a basis for development of future therapies that identify children that are genetically susceptible to respiratory disorders. PUBLIC HEALTH RELEVANCE: It is widely accepted that exposure to environmental tobacco smoke causes development and exacerbation of respiratory disorders, including asthma. While much research has been done to identify genes relevant to asthma, very limited research has focused on genetics of susceptibility to tobacco smoke exposures and subsequent asthma development. This study is specifically designed to identify genetic variation that affects biomarkers of tobacco smoke exposure and responses to oxidative stress with respect to asthma development, which will empower the search for targeted, personalized therapies, making the public health impact of this application quite significant.