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）的主要环境风险因素;然而，COPD的发展在吸烟者中存在显著差异，遗传因素可能影响这种差异。候选基因关联研究已经确定了几个潜在的COPD易感基因，全基因组关联研究有望确认多个COPD易感基因座。然而，关联研究通常不能识别相关基因中的功能变体。此外，罕见变异可能导致COPD易感性，可获得的样本量的相关性研究无法评估其影响。在波士顿早发性COPD研究中，定位克隆工作定位了几个潜在的COPD易感基因座，本研究中的罕见变异分析确定了弹性蛋白中可能影响COPD易感性的潜在功能变异。为了确定影响COPD易感性的罕见和常见遗传变异，我们将对从先前和正在进行的遗传关联研究中确定的10个候选基因进行密集重测序。为了全面表征这些候选基因的遗传变异，将在三组病例对照受试者中对这10个基因的全基因组序列进行重测序：A）180名严重的早发性COPD先证者和180名其吸烟亲属，其FEV 1值正常; B）200例国家肺气肿治疗试验（NETT）COPD病例和200例标准老化研究（NAS）吸烟对照受试者;以及200例国际COPD遗传学网络（ICGN）COPD病例和200例ICGN吸烟对照受试者。将通过比较COPD病例和对照中非同义SNP的频率进行罕见变异分析。将在五个人群中检测常见变异的遗传关联：A）NETT病例和NAS对照; B）两组波士顿早发性COPD研究家族; c）ICGN家族; d）非裔美国人COPD病例和对照。通过比较不同基因型间的异源RNA（前mRNA）水平和进行等位基因不平衡表达分析，检测潜在功能性罕见和常见变体对早发COPD先证者淋巴母细胞系中基因表达的影响。如果能发现新的COPD易感基因，就能开发新的COPD药物干预措施，从而提高对COPD病理生理学的理解，并能识别易感个体。公共卫生相关性：慢性阻塞性肺疾病（COPD）可能受遗传因素的影响，但COPD的唯一已证实的遗传决定因素是严重的α 1-抗胰蛋白酶（AAT）缺乏症。为了确定COPD的新的常见和罕见遗传决定因素，将对大量COPD受试者和对照受试者的潜在易感基因进行重新测序。将在多个人群中进行常见变异的遗传关联研究，并对已识别的变异进行功能研究。

DESCRIPTION (provided by applicant): Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD); however, the development of COPD is markedly variable among smokers, and genetic factors likely influence this variability. Candidate gene association studies have identified several potential COPD susceptibility genes, and genome-wide association studies promise to confirm multiple COPD susceptibility loci. However, association studies typically do not identify the functional variants in associated genes. Moreover, rare variants may contribute to COPD susceptibility, and association studies of attainable sample sizes cannot assess their impact. In the Boston Early-Onset COPD Study, positional cloning efforts have localized several potential COPD susceptibility loci, and rare variant analysis in this study has identified a potentially functional variant in elastin which may influence COPD susceptibility. In order to identify both rare and common genetic variants influencing COPD susceptibility, we will perform dense resequencing of 10 candidate genes identified from previous and ongoing genetic association studies. To characterize the genetic variation of these candidate genes comprehensively, resequencing of the complete genomic sequence of these 10 genes will be performed in three sets of case-control subjects: A) 180 severe, early-onset COPD probands and 180 of their smoking relatives with normal FEV1 values; b) 200 National Emphysema Treatment Trial (NETT) COPD cases and 200 Normative Aging Study (NAS) smoking control subjects; and 200 International COPD Genetics Network (ICGN) COPD cases and 200 ICGN smoking control subjects. Rare variant analysis will be performed by comparing the frequency of non-synonymous SNPs in COPD cases and controls. Common variants will be tested for genetic association in five populations: A) NETT cases and NAS controls; b) two sets of Boston Early-Onset COPD Study families; c) ICGN families; and d) African-American COPD cases and controls. Potentially functional rare and common variants will be tested for their effects on gene expression in lymphoblastoid cell lines of early-onset COPD probands by comparing heteronuclear RNA (pre- mRNA) levels across genotypes and by performing allelic imbalance expression analysis. If novel COPD susceptibility genes can be found, new pharmacological interventions for COPD could be developed, improved understanding of COPD pathophysiology could result, and susceptible individuals could be identified. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is likely influenced by genetic factors, but the only proven genetic determinant of COPD is severe alpha 1-antitrypsin (AAT) deficiency. In order to identify novel common and rare genetic determinants of COPD, resequencing potential susceptibility genes in large numbers of COPD and control subjects will be performed. Genetic association studies of common variants will be undertaken in multiple populations, and functional studies of identified variants will be performed.