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.
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