INVESTIGATION OF THE GENETICS OF ASTHMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 哮喘是一种常见的慢性肺部炎症性疾病，受遗传和环境因素的影响。作为CSGA的一部分，我们使用临床表型寻找影响哮喘易感性的基因。尽管还没有建立明确的联系，但已经发现了许多具有暗示意义的染色体区域。我们假设哮喘是一种复杂的疾病，包括遗传和生理方面的因素，包括特应性、呼吸道高反应性和炎症。我们拥有由多代大家族(明尼苏达家族)组成的独特资源，有了这些资源，我们可以假设更大的遗传同质性，使用多组分表型来改善表型，并使其更容易发生哮喘。这项提案的总体目标是确定哮喘是一种独特的疾病还是一组不同的疾病，并确定导致它们发展的基因。这些目标将通过以下具体目标来实现。1.建立易患哮喘的数量性状，并对这些性状在明尼苏达家系中进行统计聚类分析。2.利用多点连锁分析，确定这些多组分表型的染色体区域。3.通过基因精细定位和DNA序列分析，在这些定位区域中寻找与哮喘易感成分相关的候选基因。这项研究将利用已经通过CSGA收集的关于家庭的广泛数据和一种新的方法来识别哮喘易感基因。这将是识别可用于预测性遗传分析和开发针对这一常见医学问题的药物靶标的基因的第一步。 根据这些先前的方案，已确诊患有哮喘的受试者将被邀请来GCRC对他们呼出的空气进行一氧化氮(NO)分析，并捐赠30毫升的血液样本进行细胞研究。我们将要求GCRC测量受试者的生命体征并抽血，但GCRC将由过敏和哮喘项目工作人员进行No分析。来自我们以前研究的家庭和其他新受试者的其他成员将被要求接受确定，包括完成呼吸健康问卷、肺功能测试(乙酰甲胆碱挑战和/或支气管可逆性)、14种常见过敏原的皮肤测试、IgE水平和DNA分离的抽血(940毫升)，此外不进行分析和献血(30毫升)用于细胞研究。GCRC将再次被要求测量生命体征并抽取血样。所有其他测试将由过敏和哮喘项目工作人员在GCRC中进行。

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. Asthma is common, chronic inflammatory disorder of the lungs influenced by genetic and environmental factors. As part of the CSGA, we have searched for genes that influence asthma susceptibility using clinical phenotypes. Numerous suggestive chromosomal areas have been found, though no clear linkages have been established. We hypothesize that asthma is a complex condition both with respect to its inheritance and phathophysiology, including the elements of atopy, airways hyperreactivity adn inflammation. We have a unique resource comprised of large, multi-generation families (Minnesota Families), with which we can assume greater genetic homogeneity, improve phenotypes using multi-component phenotypespredisposing to the development of asthma. The overall goals of this proposal are to determine if asthma is a unique disease or a cluster of distinct disorders and identfy the genes rresponsible for their development. These goals will be pursued in the following specific aims. 1. Establish quantitative traits predisposing to asthma, and apply statistical cluster analyses to these traits among the Minnesota Families., 2. Identify the chromosomal regions responsible for these multi-component phenotypes, using multipoint linkage analyses. 3. Identify candidate genes in these mapped areas responsible for the components predisposing to asthma by using genetic fine mapping and DNA sequence analysis. This study will utilize the extensive data already collected on families through the CSGA and a novel approach to identify asthma susceptibility genes. This will be the first step in the identification of genes that can be used for predictive genetic analyses and development of drug targets for this common medical problem. Subjects alreday ascertained for asthma under these prior protocols will be invited to come to GCRC to have nitric oxide(NO) analysis of their exhaled air and to donate a 30 cc blood sample for cellular studies. We will ask the GCRC to measure the subject's vital signs and to draw this blood, but the No analysis will be performed in GCRC by a memeber of the Allergy & Asthma Program staff. Additional members form our previously studied families and other new subjects will be asked to undergo ascertainment, including completion of a respiratory health questionnaire, pulmonary function testing (methacholine challenge and / or broncho reversibility), skin testing to 14 common allergens, and a blood draw 940cc) for IgE levels and DNA isolation in addition to NO analysis and donating blood (30 cc) for cellular studies. Again, GCRC will be asked to measure vital signs and to draw the blood sample. All other testing will be performed in the GCRC by a member of the Allergy & Asthma Program staff.