Asthma diagnosis and treatment
Salmeterol response is not affected by β2-adrenergic receptor genotype in subjects with persistent asthma

https://doi.org/10.1016/j.jaci.2006.06.036Get rights and content

Background

Recent studies suggest that there might be an association between albuterol use and worsening asthma in patients homozygous for arginine (Arg/Arg) at codon 16 of the β-receptor. However, it is not known whether similar responses occur in Arg/Arg patients receiving long-acting β2-agonists.

Objective

We sought to evaluate the effects of variation in the β2-adrenergic receptor gene (ADRB2) on clinical response to salmeterol administered with fluticasone propionate.

Methods

Subjects (n = 183) currently receiving short-acting β2-agonists were randomized to twice-daily therapy with salmeterol, 50 μg, administered with fluticasone propionate, 100 μg, in a single inhaler or daily therapy with montelukast for 12 weeks, followed by a 2- to 4-day run-out period.

Results

There was sustained and significant improvement (P < .001) over baseline in all measures of asthma control in subjects receiving salmeterol, regardless of Arg16Gly genotype. Morning peak expiratory flow in subjects with the Arg/Arg genotype showed 89.0 ± 16.1 L/min improvement over baseline compared with 93.7 ± 12.7 L/min for Gly/Gly subjects and 92.5 ± 11.9 L/min for Arg/Gly subjects. Pairwise changes were similar for Arg/Arg compared with Gly/Gly or Arg/Gly genotypes (estimated differences, 4.7 L/min and 3.5 L/min, respectively). Responses did not appear to be modified by haplotype pairs. During the run-out period, all subjects had predictable and similar decreases in measures of asthma control, with no differences between genotypes.

Conclusion

Response to salmeterol does not vary between ADRB2 genotypes after chronic dosing with an inhaled corticosteroid.

Clinical implications

Analyses from this study indicate that genetic polymorphisms leading to Arg16Gly sequence changes within the β2-adrenergic receptor do not affect patients' responses to recommended asthma therapy with salmeterol and fluticasone propionate.

Section snippets

Subjects

Data from 2 identical studies, with results published in 2001 and 2002, in which DNA was collected were used for these analyses.19, 20 The replicate trials were designed to evaluate the efficacy and safety of fluticasone propionate/salmeterol (FSC), 100/50 μg Diskus (GlaxoSmithKline, Research Triangle Park, NC), in adolescent and adult subjects whose asthma was inadequately controlled with SABAs alone. Subjects were eligible for inclusion if they were 15 years of age or older and had a history

Baseline distributions

Genetic samples were available for 183 (43%) FSC recipients from the 2 identical studies. The distribution of the BUP-Cys/Arg, Arg16Gly, Gln27Glu, and Thr164Ile genotypes were all found to be in HWE. ADRB2 haplotype frequencies from unphased genotypes were estimated, and haplotype pairs were assigned to white individuals. Haplotype frequencies were not estimated in the other ethnic groups because of the small sample size.

There were no significant differences in baseline demographic, clinical,

Discussion

The results of the current study do not indicate a differential effect of ADRB2 polymorphisms on response to FSC therapy in subjects with asthma in this study. Prior studies suggest that the therapeutic responses to regularly scheduled therapy with short-acting bronchodilators vary as a result of genetic polymorphisms involving a variation at the 16th amino acid position of the β2-AR. A recent report by Wechsler et al16 analyzed data from the Salmeterol or Corticosteroids (SOCS) and Salmeterol

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    Disclosure of potential conflict of interest: E. R. Bleecker has received grant support from Altana, AstraZeneca, Boehringer-Ingelheim, Centocor, Genentech, GlaxoSmithKline, and Novartis; has consultant arrangements with Aerovance, Altana, AstraZeneca, Centocor, Critical Therapeutics, Genentech, GlaxoSmithKline, and Novartis; and is on the speakers' bureau for AstraZeneca, GlaxoSmithKline, Genentech, and Merck. M. Klotsman and S. W. Yancey are both employed by and own stock in GlaxoSmithKline. W. H. Anderson, P. M. Dorinsky, L. A. Baitinger, and L. D. Edwards all are employed by GlaxoSmithKline.

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