Implications of pharmacogenomics in the current and future treatment of asthma.

Abstract

For more than a generation, managed care has attempted to eliminate variation in care delivery in the hope of producing predictable outcomes. But the population-based, guideline-driven approach may not have fully appreciated the importance of individual behavior (adherence) and environment, as well as individual genetic makeup. Genetic variation in response to currently recommended therapies may require tailoring medication regimens to the individual patient to achieve optimal outcomes. To review the pharmacogenomics of asthma and how they impact the medications utilized for its treatment. A search of PubMed that included the time period from January 1991 through September 2005 and the key terms: asthma pharmacogenetics, asthma genetics, asthma response variability, asthma glucocorticoid resistance, asthma steroid-unresponsive, asthma control, beta-agonist genomics, beta 2-receptor abnormalities, asthma genotypes, and leukotriene inhibitor polymorphisms produced 105 articles. Forty-five were rejected for this subject review by failing the following criteria: (1) results in humans, not animals, (2) provide information about clinical implications as well as description of molecular and cellular mechanism of action or the site of action on the gene, and (3) preference for manuscripts that quantified information/ results over those that just stated that there were observed differences. The remaining 60 references were reviewed, and 7 references were added after peer review. There are now limited examples of gene polymorphisms that can influence responses to beta 2-agonists, glucocorticosteroids, and leukotriene modifiers in patients with asthma. Gene mutations that are known to alter the response to asthma therapy include Arg/Arg atr position 16, mutations of LTC4S, ALOX5, and GR/NR3C1, increased expression of GR , CRHR1 variants, and mutations in CYP1A2 (-22964 [G/A]), and T 314 allele for histamine N-methyltransferase. Some of the effects associated with these mutations are increased/decreased response to therapy, glucocorticoid resistance, decreased theophylline clearance and possible toxicity, and increased bronchoconstriction. Understanding the impact of genetic variations on response to therapy may ultimately improve treatment outcomes for patients with asthma. However, despite substantial progress, no individual gene polymorphisms have been associated with altered responses to asthma treatment in large numbers of patients. It is not yet possible to tailor medication therapy for asthma based on genetic characteristics of individual patients.