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Treatment Heterogeneity in Asthma

Genetics of Response to Leukotriene Modifiers

  • Respiratory Disorders
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Abstract

Despite advances in treatment, asthma continues to be a significant health and economic burden. Although asthma cannot be cured, several drugs, including β2 agonists, corticosteroids, and leukotriene (LT) modifiers, are well tolerated and effective in minimizing symptoms, improving lung function, and preventing exacerbations. However, inter-patient variability in response to asthma drugs limits their effectiveness. It has been estimated that 60–80% of this inter-patient variability may be attributable to genetic variation. LT modifiers, in particular, have been associated with heterogeneity in response. These drugs exert their action by inhibiting the activity of cysteinyl leukotrienes (CysLTs), which are potent bronchoconstrictors and pro-inflammatory agents. Two classes of LT modifiers are 5-lipoxygenase (ALOX5) inhibitors (zileuton) and leukotriene receptor antagonists (LTRAs) [montelukast, pranlukast, and zarfirlukast]. LT modifiers can be used as alternatives to low-dose inhaled corticosteroids (ICS) in mild persistent asthma, as add-on therapy to low- to medium-dose ICS in moderate persistent asthma, and as add-on to high-dose ICS and a long-acting β2 agonist in severe persistent asthma. At least six genes encode key proteins in the LT pathway: arachidonate 5-lipoxygenase (ALOX5), ALOX5 activating protein (ALOX5AP [FLAP]), leukotriene A4 hydrolase (LTA4H), LTC4 synthase (LTC4S), the ATP-binding cassette family member ABCC1 (multidrug resistance protein 1 [MRP1]), and cysteinyl leukotriene receptor 1 (CYSLTR1). Studies have reported that genetic variation in ALOX5, LTA4H, LTC4S, and ABCC1 influences response to LT modifiers. Plasma concentrations of LTRAs vary considerably among patients. Physio-chemical characteristics make it likely that membrane efflux and uptake transporters mediate the absorption of LTRAs into the systemic circulation following oral administration. Genes that encode efflux and uptake transport proteins harbor many variants that could influence the pharmacokinetics, and particularly the bioavailability, of LTRAs, and could contribute to heterogeneity in response. In the future, large, well designed clinical trials studying the pharmacogenetics of LT modifiers in diverse populations are warranted to determine whether a genetic signature can be developed that will accurately predict which patients will respond.

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  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgments

This work was supported by the American Lung Association Asthma Clinical Research Centers, the Nemours Research Foundation, and the National Institutes of Health (grants R01 HL 071394 and R01 HL 074755). JJL does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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  1. Centers for Clinical Pediatric Pharmacology & Pharmacogenetics, Nemours Children’s Clinic, 807 Children’s Way, Jacksonville, Florida, 32207, USA

    John J. Lima

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Lima, J.J. Treatment Heterogeneity in Asthma. Mol Diag Ther 11, 97–104 (2007). https://doi.org/10.1007/BF03256228

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