Asthma is a chronic inflammatory syndrome of the airways which afflicts over 12 million people in the USA. It is characterized physiologically by recurrent airway obstruction which resolves spontaneously or as a result of treatment, Its etiology remains unknown. Despite the lack of understanding of is etiology, there are effective treatment for asthma. There are three main classes of asthma treatment in use today, inhaled B-agonists, inhaled corticosteroids and leukotriene modifiers; a given patient may use one, two or all of these types of treatments. The treatments are not uniformly effective; they vary in their efficacy amongst individuals and there are compelling preliminary data (outlined herein) suggesting that at least half of the variance in the treatment response may be genetic in origin; our proposal is structured to identify the genes responsible for this variable response. Our proposed approach is straightforward. For each of the three major asthma treatment pathways, we will: 1)Define a panel of target genes which are likely to modify the function of the pathway; 2) Scan these targets for DNA sequence variants; 3) As variants are identified they will ascertain which, if any, alter either the level of expression of function of their encoded proteins; 4) Genotype, at loci associated with functional implications in vitro, will be ascertained in asthma patients, who have been (existing patient resources) or will be (to be acquired patient resources) phenotyped with respect to the response to treatment with the class of asthma medication of interest;5) The investigators will use a case -control association approach to define specific genotypes associated with either a salutary treatment response or lack thereof. (In newly acquired populations they will use transmission disequilibrium testing); 6) Once genotypes associated with potential pharmacogentic predictive value are defined they will collaborate with the NIH sponsored Asthma Clinical Research Network to study patients with specific genotypes to determine if they provide predictive information about treatment responses; 7) Our approach will allow us to ascertain the pharmacogenetic basis for the observed variability in asthma treatment responses.
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