In conjunction with researchers at Johns Hopkins University (David Marsh, M.D.), the investigators plan to perform genetic studies to identify the location of gene(s) that contribute to the development of asthma. The focus will be on atopic (extrinsic) asthma where there is evidence for a causal relationship between the expression of symptoms and exposure to allergen(s) implicated in the disease. It is hypothesized that atopic asthma is controlled by a limited number of genes along with numerous environmental and polygenic factors. The investigators postulate: 1) a major asthma-specific gene(s) independent of atopy; 2) a gene(s) controlling the overall genetic propensity of the individual to synthesize IgE; and 3) specific immune response genes to relevant inhaled allergens, particularly indoor allergens. Approximately 30 Caucasian and 30 African American families are studied, ascertained through multiplex sibships, and total about 600 people. Genetic linkage analysis is used to test for the existence of major asthma gene(s) and for asthma- associated genes that may control specific and nonspecific bronchial hyperactivity, eosinophil levels, IgE responsiveness, etc. The study combines both forward and reverse molecular genetic strategies, utilizing polymerase chain reaction (PCR) methodology with fluorescent-based, semi- automated analysis of micro- and mini-satellite DNA repeat sequences to investigate these genes. The investigators will test for linkage between the polymorphic genetic markers with regressive models of inheritance in which allergen levels in the homes of the asthma families will be important covariates. After establishing a linkage between an asthma gene and a polymorphic marker, the investigators will perform additional mapping studies with closely linked markers in the region. The investigators will then identify the gene using a combination of chromosomal jumping and walking strategies, constructing cDNA expression libraries, applying cytogenetic analysis and studies of homologous mammalian genes, and performing sequencing. The GCRC will be used in conjunction with this project to collect and process blood samples and to conduct extensive testing for asthma phenotypes, nonspecific bronchial hyperactivity, and specific reactivity. Since many individuals tend to have a late-phase response to allergen, a period of observation for 12-24 hours is needed.
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