0801 Answers or more questions on the role of polymorphism in response of asthma to β2-agonists?

In summary 0441 of this series, evidence is presented which indicates that individuals with arginine (instead of glycine) at codon 16 of the β2-adrenergic receptor gene (ADRB2) have impaired responses to short-acting β2-stimulants. It was also suggested in the abovementioned report that repeated use of short-acting β2-stimulants could potentially result in airway narrowing. A caveat in interpreting those data was that the results were limited to mild asthmatics on short-acting β2-stimulants, and that one should not extrapolate to other asthmatics or to longer-acting β2-stimulants. Researchers from the US and the Netherlands have addressed the latter issue in a large study involving some 2600 subjects, but if one was looking for the definitive answer to whether the arginine substitution at codon 16 is predictive of adverse events and resistance to β2-stimulants, then this research will be a disappointment. No differences were observed in terms of asthma control or exacerbations whether subjects had the arginine-arginine, arginine-glycine, or glycine-glycine genotype. However the following points are made: 1) subjects were selected on the basis of proven reversibility of airway obstruction i.e. all were by definition responsive to β2-stimulants; 2) all subjects were on treatment with one or other steroid-β2-stimulant combination. The question is now whether the previous research is technically valid but applies only to subjects with mild disease taking shorter-acting β2-stimulants, or the previous research is indeed valid but the deleterious effects of the ADBR2 polymorphism are neutralized by the combination of a steroid with a long-acting β2-stimulant? Answers to the above will require additional research before this aspect of pharmacogenetics can be put to clinical use.

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Lancet 2006; 370: 2118-25
J Allergy Clin Immunol 2005; 115: 963-72
Am J Respir Cell Mol Biol 1993; 8: 334-9