This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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