? ? We propose to perform a genome-wide association study (GWA) to identify genetic variation affecting susceptibility to asthma and related quantitative phenotypes using a panel of > 500,000 single nucleotide polymorphisms (SNPs) in case/control U.S. samples of European descent and U.S. samples of African descent with following specific aims 1) To genotype 800 cases with asthma and 600 controls without asthma of European descent and 700 cases with asthma and 450 controls without asthma of African-Americans using the Illumina HumanHap550 BeadChip platform; 2) To conduct both standard and novel genetic analyses to map genes associated with asthma and related quantitative phenotypes such as level of lung function; 3) To conduct follow-up studies in similar samples for asthma and related quantitative phenotypes. Our proposal is unique and significant for the following reasons: 1) Our cohort ascertained through the Severe Asthma Research Program represents the largest number of asthmatics with more severe disease available for genetic studies. 2) Our cohort consists of asthmatics ranging from mild to severe disease representing an excellent opportunity to study quantitative traits such as level of lung function. In addition, our population consists of adult asthmatics, which is important because children with asthma, in general, still have relatively normal lung function. Likewise, the normal (non asthmatic) population does not show the range of level of lung function present in our asthma cohorts. 3) We believe that it is crucial to include African-Americans in the primary genotyping set because of the frequency of asthma in this population and general lack of replication of studies of 'asthma' genes observed in the Caucasian population in African- Americans. This may be due to differences in allele frequencies compounded by differences in environmental exposures. 4) We have assembled a strong collaborative team by joining forces with our long term collaborators at the University of Chicago (we have worked together on the genetics of asthma for over 12 years). Our collaborators at University of Chicago including Dr Nancy Cox recently competed successfully for funding through NHLBI RFA HL-05-011 and will be one of 11 groups in the ENDGAME (ENhancing Data analysis for Genome-wide Association MEthods) consortium developing methods for GWA mapping. We expect that identification of the genes and the specific genetic variants that contribute to the development of asthma and related phenotypes will lead to new approaches for preventing and treating (thus preventing progression) this common, complex disease. (End of Abstract) ? ? ?
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