Asthma is a common disease caused by a complex interaction between genetic and environmental factors. Asthma afflicts 17 million Americans. In 1999, > 5000 persons died from asthma. Given the significant mortality and morbidity associated with asthma, it is important to continue to develop new strategies for intervention. Leukotriene antagonists are thought to be the most innovative approach to asthma therapy in 20 years. Despite their demonstrated efficacy, safety and popularity, the leukotriene antagonists are associated with a significant degree of inter-patient variability in response, which can limit their safety, efficacy and cost-effectiveness. The overall objective of this ancillary study is to elucidate the mechanisms underlying inter-patient variation in response to montelukast. Up to 80% of the variation in response to asthma drugs may be due to genetic variation. Several polymorphisms in leukotriene pathway genes can contribute to variability in response.
The specific aim of this project is to determine if polymorphisms in genes encoding 5-lipoxygenase, leukotriene A4hydrolase, LTC4 synthase, multi-drug resistance protein 1 (MRP1) and LT1 receptor proteins are determinants of response to montelukast treatment. We will collect DNA from patients participating in a parent clinical trial entitled: Effectiveness of Low Dose Theophylline as Add-On Therapy in the Treatment of Asthma (LoDo Trial). 627 patients from 19 Asthma Clinical Research Centers will be randomly assigned to receive placebo, or low dose theophylline (300 mg/day) or montelukast, 10 mg daily, for 6 months. Stepwise Linear and Poisson regressions will be performed on outcomes including treatment and genetic covariates, and interaction terms between treatment arm and genetic makeup. Polymorphisms that are highly associated with response can lead to the development of genetic tests that will identify patients most likely to benefit from montelukast treatment. This information may lead to individualization of asthma medications based on the genetic make-up of the patient.
|Dahlin, A; Litonjua, A; Irvin, C G et al. (2016) Genome-wide association study of leukotriene modifier response in asthma. Pharmacogenomics J 16:151-7|
|Dahlin, Amber; Litonjua, Augusto; Lima, John J et al. (2015) Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma. PLoS One 10:e0129385|
|Duan, Q L; Lasky-Su, J; Himes, B E et al. (2014) A genome-wide association study of bronchodilator response in asthmatics. Pharmacogenomics J 14:41-7|
|Mougey, E B; Chen, C; Tantisira, K G et al. (2013) Pharmacogenetics of asthma controller treatment. Pharmacogenomics J 13:242-50|
|Duan, Q L; Du, R; Lasky-Su, J et al. (2013) A polymorphism in the thyroid hormone receptor gene is associated with bronchodilator response in asthmatics. Pharmacogenomics J 13:130-6|
|Hirota, Tomomitsu; Takahashi, Atsushi; Kubo, Michiaki et al. (2011) Genome-wide association study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat Genet 43:893-6|
|Wu, Ann Chen; Himes, Blanca E; Lasky-Su, Jessica et al. (2010) Development of a Pharmacogenetic Predictive Test in asthma: proof of concept. Pharmacogenet Genomics 20:86-93|
|Mougey, Edward B; Feng, Hua; Castro, Mario et al. (2009) Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet Genomics 19:129-38|
|Lima, John J; Blake, Kathryn V; Tantisira, Kelan G et al. (2009) Pharmacogenetics of asthma. Curr Opin Pulm Med 15:57-62|
|Poon, Audrey H; Tantisira, Kelan G; Litonjua, Augusto A et al. (2008) Association of corticotropin-releasing hormone receptor-2 genetic variants with acute bronchodilator response in asthma. Pharmacogenet Genomics 18:373-82|
Showing the most recent 10 out of 16 publications