Fine Mapping of COPD Susceptibility Genes

描述（由申请人提供）：吸烟是慢性阻塞性肺疾病（COPD）发展的主要环境风险因素；然而，慢性阻塞性肺病的发展在吸烟者中存在显著差异。除严重α - 1-抗胰蛋白酶缺乏症外，COPD的遗传决定因素尚未得到证实。在波士顿早发性COPD研究中，使用短串联重复序列标记的基因组扫描连锁分析已经鉴定出两个与COPD相关表型有显著连锁的区域和其他几个提示连锁的区域。为了确定这些染色体区域内的COPD遗传决定因素，我们将对分布在整个连锁区域的snp进行精细的关联分析。我们将招募更多的早发性COPD家系，以复制先前基因组扫描的连锁区域，并增加基于家族关联研究的样本量。在两个连锁区域内，将在两个COPD病例池（波士顿早发性COPD研究先发者和国家肺气肿治疗试验病例）和两个对照受试者池（规范老龄化研究和护士健康研究）中以30 kb的间隔系统地进行snp基因分型。对于在病例和对照池之间显示出显著等位基因频率差异的snp，将对池中的个体成员进行基因分型，以确认这些snp与COPD之间的关联。这些已证实的SNP关联将在早发性COPD谱系中使用基于家族的关联分析进行重复性测试。对于与COPD相关表型具有重复关联的snp，将在基于家庭和病例对照的样本中鉴定相邻snp并进行基因分型，以确定影响COPD发展的关键snp和单倍型。通过强调链接和关联结果的复制，将增加稳健和有效发现的可能性。如果通过连锁和关联分析发现新的COPD易感基因，可以开发新的COPD药物干预措施，提高对COPD病理生理的理解，并可以识别易感个体。

DESCRIPTION (provided by applicant): Cigarette smoking is the major environmental risk factor for the development of chronic obstructive pulmonary disease (COPD); however, the development of COPD is markedly variable among smokers. Genetic determinants of COPD other than severe alpha 1-antitrypsin deficiency are unproven. In the Boston Early-Onset COPD Study, genome scan linkage analysis with short tandem repeat markers has led to the identification of two regions of significant linkage and several other regions of suggestive linkage to COPD-related phenotypes. To identify the COPD genetic determinants within these chromosomal regions, we will perform fine mapping with association analysis of SNPs distributed throughout the linkage regions. We will enroll additional early-onset COPD pedigrees to replicate linkage regions from the previous genome scan and to increase the sample size for family-based association studies. Within two regions of linkage, SNPs will be systematically genotyped at 30 kb intervals in two pools of COPD cases (Boston Early-Onset COPD Study probands and National Emphysema Treatment Trial cases) and two pools of control subjects (Normative Aging Study and Nurses Health Study). For SNPs that demonstrate substantial allele frequency differences between the case and control pools, individual members of the pools will be genotyped to confirm the association between those SNPs and COPD. These confirmed SNP associations will be tested for replication using family-based association analysis in early-onset COPD pedigrees. For SNPs with replicated associations to COPD-related phenotypes, adjacent SNPs will be identified and genotyped in both family-based and case-control samples in order to identify key SNPs and haplotypes influencing the development of COPD. By emphasizing replication of both linkage and association results, the likelihood of robust and valid findings will be increased. If novel COPD susceptibility genes can be found following linkage and association analysis, new pharmacological interventions for COPD could be developed, improved understanding of COPD pathophysiology could result, and susceptible individuals could be identified.