INVESTIGATION OF THE GENETICS OF ASTHMA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 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，我们使用临床表型来寻找影响哮喘易感性的基因。许多暗示性的染色体区域已经被发现，虽然没有明确的联系已经建立。我们假设哮喘在遗传和病理生理学方面是一种复杂的疾病，包括特应性、气道高反应性和炎症。我们有一个独特的资源，包括大型，多代家庭（明尼苏达州的家庭），我们可以承担更大的遗传同质性，改善表型使用多组分表型，诱发哮喘的发展。这项计划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，并确定导致其发展的基因。这些目标将在以下具体目标中实现。1.建立哮喘易感的数量性状，并对明尼苏达州家庭中的这些性状进行统计聚类分析。2.使用多点连锁分析来识别导致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，确定这些定位区域中负责哮喘易感成分的候选基因。这项研究将利用通过CSGA和一种新的方法已经收集的广泛的家庭数据来确定哮喘易感基因。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点的基因的第一步。 根据这些先前方案确定患有哮喘的受试者将被邀请到GCRC对其呼出气体进行一氧化氮（NO）分析，并捐献30 cc血液样本用于细胞研究。我们将要求GCRC测量受试者的生命体征并抽取血液，但将由过敏和哮喘项目工作人员在GCRC中进行No分析。来自我们先前研究的家庭的其他成员和其他新的受试者将被要求接受确认，包括完成呼吸健康问卷，肺功能测试，（乙酰甲胆碱激发和/或支气管可逆性），对14种常见过敏原进行皮肤测试，以及抽血（940 cc）用于IgE水平和DNA分离，此外还进行NO分析和献血（30 cc）用于细胞研究。同样，将要求GCRC测量生命体征并抽取血液样本。所有其他测试将由过敏和哮喘项目工作人员在GCRC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.