PHAT Profile

Pharmacogenetics of Asthma Treatment

Abstract (July, 2005 Update)

Goals

Our grant uses a genotype to phenotype approach to asthma pharmacogenetics. It has been estimated that as many as one-half of asthmatic patients do not respond to treatment with β2-agonists, glucocorticoids, or leukotriene antagonists. The principle hypothesis of this proposal is that genetics can be used to predict whether an individual with asthma will have a beneficial vs. a poor response to specific asthma therapies. In support of this hypothesis, our laboratories have successfully used a genotype to phenotype candidate gene approach to identify genetic variants that are associated with treatment-specific responses to all three major classes of asthma therapeutics. Despite this success, no variation at the single SNP or haplotypic level in any single gene has been discovered that can explain a large enough proportion of the phenotypic variance to be clinically predictive for any asthma drug. Thus, the major goal of this proposal is to identify a set of robust and clinically significant genetic variants that can predict therapeutic response to asthma drugs. Our goal is to replace the current "trial-and-error" paradigm of asthma treatment with an inexpensive, rapid, and reliable pharmacogenetic test of non-response, to inhaled steroids or β2-agonists. As such, we have structured our Specific Aims as follows:

1. We will choose candidate genes in the β2-adrenergic and glucocorticoid pathways, identify genetic variants in these genes, genotype individuals in clinical drug trials at these loci, and perform association testing to determine which genetic variants are associated with an altered therapeutic response. The genes with positive association results that are replicated in multiple study populations will be comprehensively resequenced for functional assessment.
2. Robust and replicated pharmacogenetic associations will be explored at the molecular, cellular, and integrative level to establish functional variants and pharmacogenetic mechanisms.
3. We will develop and validate a predictive test of asthma therapeutic response to β2-adrenergic and glucocorticoid drugs.

Additional aims relate to our collaboration with PharmGKB and the PGRN and helping investigators interested in pharmacogenetics. DNA samples and matching phenotypic data have been collected from 3,698 asthmatics enrolled in 12 well-designed asthma drug trials. This allows us to replicate association findings and validate our pharmacogenetic test in multiple populations.If successful, our research should directly benefit patient care by lowering morbidity and mortality and substantially decreasing health care costs.

Progress

We have a preliminary screening data on 1041 SNP in 225 genes that is currently being analyzed at the first stage of our new screening algorithm. This first phase will be completed by July and the second part of the validation process for this set of genes will be completed by September and the third or final validation phase for specific aim 1 will be completed by November for this set of genes. We will be adding new genes to this process at that time. We have also made progress on specific aim 2: identifying functional variants. For this aim we have developed a mouse model for steroid treatment response and we have sequenced over 700 subjects to identify the haplotypes and functional variants in ADRB2. We have also made progress on specific aim 3 with a prototype predictive test based on our first 51 genes and 291 SNPs.

Experimental Plans

We plan to pursue the novel variants we have found in the 3'UTR of the ADRB2 gene and also the subhaplotypes in our mouse model. We also are testing CRHR1 and CRHR2 in our steroid treatment response mouse to find functional variants. We are also pursuing other GC pathway genes in functional assays. We intend to publish our positive replicated genetic associations based on the first 225 genes we have screened and recomputed are prototype predictive tests for steroid and beta agonist treatment response. We expect to complete this work in the first year of the grant.

PHAT Team

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