Epidemiologic data indicate that a positive family history is a major risk factor for asthma, yet genes that confer susceptibility to asthma are largely unknown. As a participating center in the Collaborative Study of the Genetics of Asthma (CSGA; HL49596), we are conducting a genome-wide search for asthma genes in the Hutterites, an inbred Caucasian population that is well characterized with respect to asthma phenotypes. Our genome- wide search has already identified two chromosomal regions that show evidence for linkage to asthma and two additional regions that show preliminary evidence of linkage in the Hutterites. The major objective of the proposed investigation is to identify and characterize specific genes and alleles in these, and other, linked regions that confer susceptibility to asthma or an associated phenotype. We propose to complete higher resolution maps using short tandem repeat polymorphisms (STRPs) (spaced about 2 cM intervals) in regions that are linked to asthma or one of the asthma-associated phenotypes, including bronchial hyperresponsiveness (BHR), total serum IgE, multi-RAST IgE, and skin test reactivity. STRP haplotypes in linked regions will be determined in families and linkage disequilibrium mapping will be used to identify 0.3 cM to 1.0 cM candidate regions that include disease-susceptibility loci. A systematic search for DNA sequence variations (mutations or polymorphisms) will be conducted in genes or transcripts in the candidate regions. Associations between genotype and phenotype will be confirmed in affected and unaffected Hutterites to establish the role of specific alleles in the disease process. Once susceptibility alleles are identified, DNA from members of ethnically heterogeneous, outbred asthma families will be studied to determine whether the same alleles or other alleles in the same genes also influence asthma and the asthma-associated phenotypes in outbred individuals. Identifying the specific genes that influence asthma and associated phenotypes is the next step in elucidating the genetic contribution to the pathophysiologic processes that underlie this disease.
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