Genome-wide and Linkage Study of Quantitative Emphysema Phenotypes

描述(申请人提供)：此申请是对挑战区04-HL-104的回应，“对现有数据进行二次分析，以回答重要的临床和预防医学研究问题。”具体主题是#8，“分析与风险因素和疾病相关的遗传标记与它们的遗传和环境背景有关，以及如何利用这些标记为预防医学和临床护理提供信息。肺气肿和慢性阻塞性肺疾病(COPD)加在一起，将很快超过中风，成为美国第三大死亡原因，其中非欧洲血统的美国人死亡人数增加最多。肺气肿的定义是肺泡壁破坏的永久性空间扩大；慢性阻塞性肺疾病的定义是气流受限，但不完全可逆。SERPINA1基因突变会导致全小叶性肺气肿，但占病例的1%。吸烟是小叶中心型肺气肿的主要环境原因，但只有不到三分之一的重度吸烟者会患上这两种疾病，这可能表明存在遗传风险。然而，没有其他可能导致肺气肿的基因被证实，部分原因是在基因分型密集的队列中缺乏对肺气肿的定量测量。动脉粥样硬化多种族研究(MESA)和MESA家族研究对6814名年龄在45-84岁之间、没有临床心血管疾病的参与者和595个家庭(2077名参与者)进行了心脏计算机断层扫描(CT)。MESA家族研究进行了亚临床动脉粥样硬化的连锁研究，两项研究都将获得100万个SNP全基因组关联研究(GWAS)数据。梅萨-肺研究测量并验证了3965名梅萨参与者心脏CT扫描肺部区域的定量肺气肿表型。然而，这一样本量仅足以检测出GWAS水平上的较大相关性。因此，我们建议在心脏CT扫描上测量其他2579名MESA参与者和2077名MESA家族研究参与者的肺气肿表型。然后，我们将利用现有的全基因组连锁和GWAS数据，对595个非洲和西班牙裔家族以及6,544个非洲、西班牙裔、欧洲或中国血统的参与者进行统计遗传分析：1)基于家族的连锁和GWAS在Mesa-Family研究中用于定量肺气肿表型，以及2)根据吸烟史对MESA队列中分层前后的定量肺气肿表型进行GWAS分析。这项应用建议结合梅萨、梅萨肺和梅萨家庭研究的数据，并添加有选择的新数据，以在基于人群的队列和家庭研究的8120名参与者中对肺气肿的遗传基础进行新的、高成本效益的研究。拟议的肺气肿表型定量研究的独特之处在于采用了队列而不是病例对照设计，包括非吸烟者，并纳入了肺气肿患病率上升最快的少数族裔群体。拟议的目标将研究基因组中DNA变异和吸烟史修饰的作用，以识别风险变异，并为未来揭示疾病途径和治疗靶点的功能和基因/表型研究提供洞察力。肺气肿将很快取代中风成为美国第三大死亡原因，非洲裔美国人和亚洲人的肺气肿死亡率增幅最大。治疗选择很少，部分原因是对其原因的了解有限。吸烟会导致某些类型的肺气肿，但大多数吸烟者不会患上肺气肿，这可能表明存在遗传风险。这项研究建议在一个大型多民族队列和家庭研究(n=8,120)中利用100万个SNP全基因组和连锁数据来测量现有CT扫描上的肺气肿，以检查肺气肿的遗传风险，这可能有助于更好地了解肺气肿的风险。

DESCRIPTION (provided by applicant): This application is in response to Challenge Area 04-HL-104, "Perform secondary analyses of existing data to answer important clinical and preventive medicine research questions." The specific topic is #8, "Analysis of genetic markers related to risk factors and disease in relation to their genetic and environmental context and how these may be used to inform preventive medicine and clinical care. Together, emphysema and chronic obstructive pulmonary disease (COPD) will soon surpass stroke as the third leading cause of death in the United States, with the largest increase occurring in Americans of non-European ancestry. Emphysema is defined by a permanent enlargement of airspaces with destruction of alveolar walls; COPD, by airflow limitation that is not fully reversible. Mutations in the SERPINA1 gene cause panlobular emphysema but account for <1% of cases. Smoking is the major environmental cause centrilobular emphysema, but less than one third of heavy smokers develop either disease, which may suggest a genetic risk. However, no other putatively causal genes have been confirmed for emphysema, in part due to a lack of quantitative measures of emphysema in cohorts with dense genotyping. The Multi-Ethnic Study of Atherosclerosis (MESA) and MESA-Family Studies performed cardiac computed tomography (CT) scans for 6,814 participants age 45-84 years free of clinical cardiovascular disease and 595 families (2077 participants). The MESA-Family Study performed linkage studies for subclinical atherosclerosis, and one million SNP genome wide association study (GWAS) data will be available for both studies. The MESA-Lung Study measured and validated quantitative emphysema phenotypes on the lung regions of cardiac CT scans for 3,965 MESA participants. This sample size, however, is adequate to detect only large associations at GWAS levels of significance. We therefore propose to measure quantitative emphysema phenotypes on cardiac CT scans for the other 2,579 MESA participants and 2,077 MESA Family Study participants. We will then use existing genome- wide linkage and GWAS data among 595 families of African and Hispanic ancestry and 6,544 participants of African, Hispanic, European or Chinese ancestry to conduct statistical genetic analysis of: 1) family-based linkage and GWAS for quantitative emphysema phenotypes in the MESA-Family Study and 2) GWAS analyses for quantitative emphysema phenotypes in the MESA cohort before and after stratification by smoking history. This application proposes to combine data from the MESA, MESA Lung and MESA Family Studies and add selective new data to perform novel, highly cost-effective research on the genetic basis of emphysema among 8,120 participants in a population-based cohort and family study. The proposed research on quantitative emphysema phenotypes is unique in utilizing a cohort rather than case-control design, including non-smokers, and enrolling minority ethnic groups in which the prevalence of the disease in rising most rapidly. The proposed aims will examine the role of DNA variation in the genome and modification by smoking history to identify risk variants and provide insight for future functional and genotype/phenotype research that will disclose disease pathways, and therapeutic targets. Emphysema will soon overtake stroke as the third leading cause of death in the US, with the greatest increase among African-Americans and Asians. Therapeutic options are few, in part due to a limited understand of its causes. Smoking causes some types of emphysema but most smokers do not develop emphysema, which might suggest a genetic risk. This study proposes to measure emphysema on existing CT scans in a large multiethnic cohort and family study (n=8,120) with 1 million SNP genome-wide and linkage data to examine genetic risk for emphysema, which may lead to a better understanding of risk for emphysema.