Asthma and lower airway disease
Adrenergic β2-receptor genotype predisposes to exacerbations in steroid-treated asthmatic patients taking frequent albuterol or salmeterol

https://doi.org/10.1016/j.jaci.2009.07.043Get rights and content

Background

On-demand inhaled albuterol is commonly prescribed worldwide. We have shown that the Arg16 allele of the adrenergic β2-receptor agonist gene (ADRB2) predisposes to exacerbations in young asthmatic patients taking regular salmeterol.

Objective

We have now extended our previous population by 636 patients and explored the role of the Arg16 allele on asthma exacerbations in the context of the use of on-demand albuterol and regular salmeterol.

Methods

Arg/Gly status at position 16 of ADRB2 was assessed in 1182 young asthmatic patients (age, 3-22 years) from Scotland. Asthma exacerbations, use of β-agonists and other medications over the previous 6 months, and lung function were also studied.

Results

An increased risk of exacerbations per copy of he Arg16 allele was observed in asthmatic patients, regardless of treatment regimen (odds ratio [OR], 1.30; 95% CI, 1.09-1.55; P = .003). This appears to be largely due to exposure to β2-agonists because the risk of exacerbations observed in patients with the Arg16 allele was only observed in those receiving daily inhaled long- or short-acting β2-agonist treatment (OR, 1.64; 95% CI, 1.22-2.20; P = .001). In contrast, there was no genotypic risk for exacerbations in patients using inhaled β2-agonists less than once a day (OR, 1.08; 95% CI, 0.85-1.36; P = .525). The Arg16 genotype–associated risk for exacerbations was significantly different in those exposed to β2-agonists daily versus those that were not (test for interaction, P = .022).

Conclusion

The Arg16 genotype of ADRB2 is associated with exacerbations in asthmatic children and young adults exposed daily to β2-agonists, regardless of whether the exposure is to albuterol or long-acting agonists, such as salmeterol.

Section snippets

Methods

We have continued the recruitment of children with physician-diagnosed asthma for the BREATHE study beyond the publication of our initial results.7 The current dataset includes information about demographic, anthropometric, and clinical details from 1182 patients attending 29 primary care practices and 2 secondary care asthma clinics in Tayside, Scotland, from 2004-2008 (age, 3-22 years).

The study was approved by the Tayside Committee on Medical Research and Ethics. Informed consent was

Results

The population characteristics are typical of children and young adults with well-controlled asthma derived from both primary and secondary care (Table IV). We had collected data on 546 children previously7 and have now increased our study population to 1190 participants, of whom 1182 were white. Further analysis was performed on data from white participants. The data from other ethnic groups were not sufficient for further analysis. The prevalence of the Arg/Arg16 genotype was 15.3%, the

Discussion

The study shows for the first time that there is an increase in risk of exacerbations per copy of the Arg16 allele in children and young adults with asthma taking frequent (once daily or more) as-required doses of inhaled albuterol. This effect is not observed in participants with asthma who are not exposed to β2-agonist on a daily basis. The study also extends our previous findings of an increase in the risk of exacerbations per copy of the Arg16 allele in children and young adults with asthma

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    Support for the study was approved by the Gannochy Trust (Perth, Scotland), Scottish Enterprises Tayside, and the Perth and Kinross Council. C. N. A. P. is supported by the Scottish Executive Genetic Health Initiative Award.

    Disclosure of potential conflict of interest: B. J. Lipworth has provided consulting advice regarding the fluticasone/formoterol combination for Mundipharma, provided a speakers' bureau talk on budesonide formoterol for AstraZeneca and a speakers' bureau talk on heterogeneity in asthma and airway remodeling for Merck, has received research support from Merck Sharpe & Dohme and Neolab, and has provided legal consultation on formoterol equivalence for TEVA. S. Mukhopadhyay has served as an expert advisor for and received research support from Merck Sharpe & Dohme. The rest of the authors have declared that they have no conflict of interest.

    These authors contributed equally to this work.

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