Diesel, Allergens and Gene Interaction and Child Atopy

描述（由研究者提供）：该竞争性修订将严格遵守ARRA，保留研究助理的职位，并为本科生创建一个研究助理职位和一个兼职职位，并通过从美国大型公司购买基因分型服务来刺激经济。此次修订还旨在创建新的研究目标，以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。ETS暴露是儿童呼吸系统疾病的主要原因。尼古丁和可替宁测量值可作为ETS中存在的4700多种化学物质的全身暴露量的代表，其中许多具有促炎特性，包括尼古丁。ETS还诱导活性氧（ROS）和氧化应激的产生，主要由谷胱甘肽-S-转移酶（GST）家族中的酶失活。已经在与尼古丁代谢和氧化应激相关的基因中鉴定出功能多态性，其可以减少可替宁形成（并因此增加尼古丁）和ROS失活。中心假设是，尼古丁代谢和/或氧化应激相关基因中变异等位基因的携带者可能会增加全身尼古丁水平，从而导致ETS生物标志物的错误分类，以及呼吸系统疾病（包括哮喘）的患病率和恶化率增加。我们将通过以下目的来检验这一假设：1）确定尼古丁代谢基因中的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，多个基因中的变异等位基因沿着尼古丁代谢途径将导致全身尼古丁增加和可替宁形成减少，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对呼吸结果的影响。我们假设，尼古丁代谢和/或氧化应激相关基因中具有变异等位基因的儿童将增加呼吸系统疾病的患病率和加重。这项竞争性修订将评估参与CCAAPS的受试者，CCAAPS是一个特征良好的过敏性疾病高风险出生队列，其主要目的是确定柴油机尾气对儿童过敏性疾病和哮喘的影响。目前，父母队列正在从7岁儿童中收集包括哮喘在内的呼吸道疾病的客观指标，以及DNA、头发样本和父母关于ETS暴露的报告。该修订建议对尼古丁代谢和氧化应激相关基因的功能和标记单核苷酸多态性（SNP）进行基因分型，并量化头发样本中的尼古丁和可替宁。这项研究具有重要意义，因为它将提供新的信息，说明在流行病学研究中量化尼古丁和可替宁作为ETS暴露的生物标志物时需要考虑遗传组成。此外，这项研究可能为未来开发治疗方法提供基础，以确定遗传上易患呼吸系统疾病的儿童。 公共卫生相关性：人们普遍认为，暴露于环境烟草烟雾会导致呼吸系统疾病，包括哮喘的发展和恶化。虽然已经做了很多研究来鉴定与哮喘相关的基因，但是非常有限的研究集中在哮喘的遗传学上。 烟草烟雾暴露和随后的哮喘发展的易感性。这项研究专门用于确定影响烟草烟雾暴露生物标志物的遗传变异和对哮喘发展的氧化应激反应，这将有助于寻找有针对性的个性化治疗，使这种应用对公共卫生的影响非常显着。

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.