Genetic epidemiology of glutathione and CF lung disease

描述(由申请人提供)： 这项提议是一项为期五年的培训计划，旨在为首席调查员的职业生涯做好准备，成为一名对肺部疾病遗传流行病学感兴趣的独立的、以病人为导向的研究人员。通过完成这些项目以及从事临床和遗传流行病学的课程工作，候选人将发展必要的技能，以设计和实施以家庭为基础的遗传关联研究，包括基因-基因和基因-环境相互作用。该提案是肺部和重症监护医学部与公共卫生遗传学和环境卫生系之间的合作，包括囊性纤维化、遗传流行病学、环境卫生和毒理学方面的专家。这项研究的主要科学目标是分析囊性纤维化患者肺部疾病变异性的遗传决定因素。目的1是一项使用国家CF数据库的回顾性队列研究，以量化CF型对包括肺功能和死亡率在内的CF型临床表现的影响。目的2将是一项前瞻性研究，以检查严重的慢性肺病与影响谷胱甘肽合成的候选基因之间的联系和联系。DNA将从CF患者及其亲生父母那里收集。传递不平衡测试(TDT)将对寻找谷氨酰半胱氨酸连接酶催化亚单位(GLCLC)多态从父母到患有严重肺部疾病的CF患者的不平等分离的三者进行。目的3也将使用TDT研究严重的慢性肺病与谷胱甘肽-S-转移酶M1和肿瘤坏死因子-α的多态之间的关系。由于这些多态可能会影响谷胱甘肽的合成和功能，因此将采用病例研究设计和Logistic回归分析来检验与GLCLC多态有关的基因-基因交互作用。最后，在目标4中，将通过使用有效问卷和居住地点的方法，测量环境中烟草烟雾和空气污染物的暴露，以检验基因与环境的相互作用。这些项目在预测可能发展为严重肺部疾病的高易感患者以及增加我们对CF肺功能下降机制的理解方面都具有很强的临床和公共卫生意义。

DESCRIPTION (provided by applicant): This proposal is a five-year training plan designed to prepare the Principal Investigator for a career as an independent patient-oriented researcher with an interest in the genetic epidemiology of lung disease. Through the completion of these projects as well as the pursuit of course work in clinical and genetic epidemiology, the candidate will develop the necessary skills to design and implement family-based genetic association studies, including gene-gene and gene-environment interaction. The proposal is a collaboration between the Division of Pulmonary and Critical Care Medicine and the Departments of Public Health Genetics and Environmental Health and includes experts in cystic fibrosis, genetic epidemiology, environmental health and toxicology. The primary scientific goal of this research is to analyze the genetic determinants of lung disease variability in patients with cystic fibrosis (CF). Aim 1 will be a retrospective cohort study, using the National CF database, to quantify the effect of CF genotype on CF clinical manifestations, including lung function and mortality. Aim 2 will be a prospective study to examine for linkage and association between severe CF lung disease and a candidate gene that influences glutathione synthesis. DNA will be collected from CF patients and their biological parents. Transmission disequilibrium testing (TDT) will be performed on the trios looking for unequal segregation of glutayl-cysteine-ligase catalytic subunit (GLCLC) polymorphisms from parents to CF patients with severe lung disease. Aim 3 will examine for an association between severe CF lung disease and polymorphisms of glutathione-S-transferase M1 and TNF-alpha also using a TDT. As these polymorphisms may influence glutathione synthesis and function, gene-gene interaction with GLCLC polymorphisms will be examined using a case-only study design and logistic regression. Finally, in aim 4, through the use of validated questionnaires and methods of residence location, environmental exposure to tobacco smoke and air pollutants will be measured to test for gene-environment interaction. These projects have strong clinical and public health implications both in terms of predicting high-susceptibility patients that may develop severe lung disease as well as increasing our understanding of the mechanisms of CF lung function decline.