Genome-wide and Linkage Study of Quantitative Emphysema Phenotypes

描述（由申请人提供）：本申请是对挑战领域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，以及与遗传和环境背景有关的遗传标记，以及如何将这些标记用于预防医学和临床护理。”肺气肿和慢性阻塞性肺疾病（COPD）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增幅最大。肺气肿的定义是空气空间的永久性扩大和肺泡壁的破坏；慢性阻塞性肺病，通过气流限制，不完全可逆。SERPINA1基因突变引起全小叶肺气肿，但占病例的1%以下。吸烟是造成小叶中心肺气肿的主要环境因素，但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，没有其他假定的导致肺气肿的基因被证实，部分原因是在密集基因分型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45-84岁无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家族研究对亚临床动脉粥样硬化进行了连锁研究，100万个SNP基因组全关联研究（GWAS）数据将可用于这两项研究。MESA-肺研究测量并验证了3965名MESA参与者心脏CT扫描肺部区域的定量肺气肿表型。然而，该样本量仅足以检测GWAS显著性水平上的大关联。因此，我们建议对其他2,579名MESA参与者和2,077名MESA家族研究参与者的心脏CT扫描进行定量肺气肿表型测量。然后，我们将使用595个非洲和西班牙裔家庭以及6544名非洲、西班牙裔、欧洲或中国血统的参与者的现有全基因组连锁和GWAS数据进行统计遗传分析：1)MESA家族研究中基于家族的连锁和GWAS定量肺气肿表型，2)GWAS分析MESA队列中吸烟史分层前后的定量肺气肿表型。本申请拟结合MESA、MESA肺和MESA家族研究的数据，并添加选择性的新数据，在一项基于人群的队列和家庭研究中，对8120名参与者进行新颖、高成本效益的肺气肿遗传基础研究。提出的定量肺气肿表型研究的独特之处在于采用队列而不是病例对照设计，包括非吸烟者，并纳入疾病患病率上升最快的少数民族。提出的目标将检查DNA变异在基因组中的作用，并通过吸烟史来确定风险变异，并为未来的功能和基因型/表型研究提供见解，从而揭示疾病途径和治疗靶点。肺气肿将很快超过中风，成为美国第三大死亡原因，其中非洲裔美国人和亚洲人的增幅最大。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肺气肿，这可能表明有遗传风险。本研究建议在现有的大型多民族队列和家庭研究（n= 8120）中使用100万个SNP全基因组和连锁数据来测量肺气肿，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.