? Severe asthma consists of approximately 10% of asthmatics who have frequent and severe symptoms despite aggressive therapy with anti-inflammatory as well as other control medications. For this competitive renewal of our Severe Asthma Research Program (SARP), the clinical characterization of patients with severe asthma and assessment of inflammatory parameters will continue to be performed collaboratively so that data collected across the different centers can be evaluated and compared. We will determine corticosteroid responsiveness with the STAC characterization protocol to evaluate the importance of steroid resistance in severe asthma. We will contrast these more severe asthma subjects with milder asthmatics and obtain DNA samples for genetic analyses. We hypothesize that factors that cause severe asthma are caused by altered inflammatory responses that are related at least in part to polymorphisms in genes that regulate inflammation or affect airway structure. We also hypothesize that some patients develop severe asthma because of genetic differences that alter their responses to therapeutic agents. To test these hypotheses, we propose the following specific aims: (1) Collaborate with other SARP Investigators in the pharmacologic characterization of subjects to determine mechanisms responsible for corticosteroid responsiveness including high resolution CT scans and pharmacogenetics; (2) Continue to perform comprehensive characterizations of a larger set of subjects with severe and non severe asthma which will be used to discriminate severe from milder asthma; (3) Continue genetic association studies including analysis of related quantitative measures. This will include genes from our biologic studies (and those from other SARP centers) and genes in relevant pathways; (4) Perform a gene chip analysis of inflammatory genes on 200 of the most severe asthmatics and 200 of the most mild asthmatics (from all SARP sites) using the GeneChip ParAllele TrueTag 10K l& I Array run on our Affymetrix system (1,086 genes with >9000 SNPs). We feel strongly that collaborative research is necessary to meet the goals of this RFA and is crucial to genetic studies. We will continue to participate as an active member of SARP II. ? ?
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