FINE MAPPING OF COPD SUSCEPTIBILITY GENES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。慢性阻塞性肺疾病(COPD)是导致死亡的第四大原因。1吸烟是慢性阻塞性肺疾病发展的主要环境危险因素；然而，吸烟的影响存在相当大的变异性。除了吸烟的风险外，患有α1-抗胰蛋白酶缺乏症的受试者还有一个主要的COPD遗传风险因素；其他遗传风险因素尚未确定。慢性阻塞性肺疾病在α1-抗胰蛋白酶缺乏症患者中的频繁发展为蛋白水解酶-抗蛋白水解酶假说在慢性阻塞性肺疾病发病机制中的应用奠定了基础，并成为一种典型的单基因遗传病的模型。然而，许多早发性COPD患者并不缺乏α1-抗胰蛋白酶。COPD可能是一种复杂的疾病，有多种遗传和环境影响。在波士顿早发性COPD研究中，埃德温·西尔弗曼博士的研究小组已经确认了140名没有严重AAT缺乏的严重早发性COPD患者及其800多名亲属。他们发现，与有类似吸烟史的对照组相比，气流阻塞和慢性支气管炎的风险显著增加。在早发性COPD家系中，已经用短串联重复序列(STR)标记进行了基因组扫描连锁分析，并发现了两个显著连锁的区域和其他几个暗示与COPD相关表型连锁的区域。为了确定这些连接的染色体区域内的COPD遗传决定因素，Silverman博士建议对位于这些连接区域的SNP进行精细定位和关联分析。为了发现早发性COPD的易感基因并确定这些遗传决定因素是否也会影响晚年COPD，我们从其他几个人群中收集了DNA样本：1)国家肺气肿治疗试验(NETT)参与者，她们严重COPD的年龄晚于波士顿早发性COPD研究的先证者(初始对象)；2)标准老龄化研究(NAS)男性对照组，尽管有大量吸烟史，但肺活量测量正常；以及3)护士健康研究(NHS)女性对照组，有明显吸烟史但尚未被诊断为阻塞性肺病。通过病例对照和以家庭为基础的遗传流行病学方法利用这四个独特的人群，提供了识别COPD易感基因的绝佳机会。这项研究的目的是验证可识别的遗传因素，而不是阿尔法-1抗胰蛋白酶缺乏影响COPD发展的假说。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of mortality. 1 Cigarette smoking is the major environmental risk factor for the development of COPD; however, considerable variability in the effect of smoking exists. In addition to the risk from smoking, subjects with alpha 1-antitrypsin deficiency have a major genetic risk factor for COPD; other genetic risk factors have not been identified. The frequent development of COPD in individuals with alpha 1-antitrypsin deficiency has provided a foundation for the protease-antiprotease hypothesis for the pathogenesis of COPD and served as a model of a well-characterized monogenic genetic disease. However, many subjects with early-onset COPD are not alpha 1-antitrypsin deficient. COPD is likely a complex disease with multiple genetic and environmental influences. In the Boston Early-Onset COPD Study, Dr. Edwin Silverman's research group has identified 140 individuals with severe early-onset COPD, without severe AAT deficiency, and more than 800 of their relatives. They have found a significantly increased risk for airflow obstruction and chronic bronchitis compared to control subjects with similar smoking histories. Within early-onset COPD families, genome scan linkage analysis has been performed with short tandem repeat (STR) markers and have identified two regions of significant linkage and several other regions of suggestive linkage to COPD-related phenotypes. To identify the COPD genetic determinants within these linked chromosomal regions, Dr. Silverman has proposed to perform fine mapping with association analysis of SNPs located across these linkage regions. In order to find early-onset COPD susceptibility genes and to determine if those genetic determinants also influence COPD at later ages, DNA samples have been collected from several other populations: 1) National Emphysema Treatment Trial (NETT) participants, who have severe COPD at later ages than the Boston Early-Onset COPD Study probands (initial subject); 2) Normative Aging Study (NAS) male control subjects, who have normal spirometry despite substantial smoking histories; and 3) Nurses Health Study (NHS) female control subjects, who have significant smoking histories but have not been diagnosed with obstructive lung disease. Utilizing these four unique populations with case-control and family-based genetic epidemiological approaches provides an excellent opportunity to identify COPD susceptibility genes. The purpose of this study is to test the hypothesis that identifiable genetic factors, other than Alpha-1 Antitrypsin deficiency influence the development of COPD.