Severe asthma is generally defined as a chronic condition with suboptimal response to continuous high-dose inhaled or oral steroids to control inflammation (steroid resistance). It is clear that many types of steroidresistant asthma exist, which may be explained by altered glucocorticoid receptor mediated gene expression, differences in glucocorticoid receptor steroid binding affinity, or defects in other components that control assembly and function of the glucocorticoid receptor complex. The glucocorticoid receptor (GR) is only one part of a large multi-protein complex. In addition to GR, five other protein components are necessary to constitute a minimum steroid binding complex, and include heat shock protein 90 (hsp90 alpha and beta), heat shock protein 70 (hsc70 and hsp70 [1A and 1B]), heat shock protein 40 (hsp40), hsp organizing protein (hop), and p23. Genes for these eight proteins required for proper assembly of an active GR complex will be re-sequenced in a population of severe asthmatics to define polymorphisms for use in genetic association studies and determine if there are polymorphisms which may have important functional effects on expression and/or translation of these proteins. After defining these polymorphisms, mild and moderate asthmatics will be genotyped to compare allele, genotype, and haplotype frequencies and differences in tissue inflammatory markers and physiological data with that of severe asthmatics. This """"""""pathway"""""""" approach to genetic analysis will be the first and most complete dissection of the GR complex in a severe asthma population. Information gathered in this study will determine if there is an association between the GR complex and corticosteroid insensitivity in severe asthmatics and potentially provide important genetic markers that could predict how asthmatics may respond to administration of corticosteroids (pharmacogenetics). This will also lay the ground work for future functional studies using coding sequence variants identified in the GR complex proteins. ? ? ?
