BACKGROUND:

Asthma is a common disease caused by a complex interaction between genetic and environmental factors. Asthma afflicts 17 million Americans. In 1999, more than 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. Several polymorphisms in leukotriene pathway genes can contribute to variability in response. The project will 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.

The study is in response to an Request for Applications entitled Ancillary Studies in Heart, Lung, and Blood Disease Trials which was released by the NHLBI in June 2000 to conduct mechanistic studies in clinical trials related to heart, lung and blood diseases. Specifically, this initiative focuses on the utilization of patients and patient materials from such trials to study the mechanisms underlying the interventions, the mechanisms of disease pathogenesis, surrogate markers or biomarkers of disease activity and therapeutic effect and the mechanisms of human cardiopulmonary and hematologic function. Studies aimed at accelerating the development of new technologies within the context of the mechanistic investigations are also encouraged.

DESIGN NARRATIVE:

DNA will be collected 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.