Fine Mapping of a COPD Locus on Chromosome 19q

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）是美国第四大死亡原因，并且在过去二十年中，COPD的死亡率一直在增加。 吸烟是最重要的危险因素，但吸烟者之间气流阻塞的发展是可变的。 家族研究表明，遗传因素对COPD的发展有贡献，但严重的α 1-抗胰蛋白酶缺乏症是迄今为止唯一被证实的遗传风险因素。 先前的研究已经证明了COPD与染色体19 q上的区域的联系。 我们假设位于染色体19 q上的一个或多个基因影响COPD的易感性，特别是在吸烟者中，并且这些基因可以使用高分辨率单核苷酸多态性（SNP）作图策略来识别。 为了验证这一假设，我们建议在两个病例对照人群中对整个连锁区域的大约1500个SNP进行基因分型。 在单独的遗传关联分析中，将波士顿早发性COPD研究的病例与护士健康研究的对照进行比较，将国家肺气肿治疗试验的病例与规范性衰老研究的对照进行比较。 将在波士顿早发性COPD研究的扩展家系中验证阳性相关性。 在两个病例对照样本中使用高密度SNP作图和关联分析，并在基于家族的研究设计中进行验证，应允许识别染色体19 q上的COPD易感基因座，这可能会导致更好地了解COPD发病机制，并可能突出新的COPD治疗途径和靶点。 拟议的项目将通过一系列课程、研讨会和遗传流行病学、分子遗传学和生物信息学领域的监督研究，培训首席研究员成为气道疾病遗传流行病学领域的独立研究员。

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, and the mortality rate from COPD has been increasing over the past two decades. Cigarette smoking is the most important risk factor, but the development of airflow obstruction among smokers is variable. Family studies have suggested a genetic contribution to the development of COPD, but severe alpha 1-antitrypsin deficiency has been the only proven genetic risk factor to date. Previous studies have demonstrated evidence for linkage of COPD to a region on chromosome 19q. We hypothesize that one or more genes that are located on chromosome 19q influence susceptibility to COPD, especially in cigarette smokers, and that these genes can be identified using a high-resolution single nucleotide polymorphism (SNP) mapping strategy. To test this hypothesis, we propose to genotype approximately 1500 SNPs across the linked region in two case control populations. In separate genetic association analyses, cases from the Boston Early-Onset COPD Study will be compared to controls from the Nurses Health Study, and cases from the National Emphysema Treatment Trial will be compared to controls from the Normative Aging Study. Positive associations will be validated in the extended pedigrees from the Boston Early-Onset COPD Study. The use of high-density SNP mapping with association analysis in two case-control samples and validation in a family-based study design should permit the identification of a COPD-susceptibility locus on chromosome 19q, which could result in better understanding of COPD pathogenesis and could highlight pathways and targets for new COPD therapies. The proposed project will train the principal investigator to become an independent investigator in the field of genetic epidemiology of airways disease, through a series of courses, seminars, and supervised research in the areas of genetic epidemiology, molecular genetics, and bioinformatics.