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Doi:10.1016/j.jaci.2006.06.036

Original articles Salmeterol response is not affected byb2-adrenergic receptor genotype in subjects with persistent asthma Eugene R. Bleecker, MD,a Steven W. Yancey, MS,b Leslie A. Baitinger, MS,b Lisa D. Edwards, PhD,b Michael Klotsman, PhD,b Wayne H. Anderson, PhD,b and Paul M. Dorinsky, MDb Winston-Salem and Research Triangle Park, NC Background: Recent studies suggest that there might be an Conclusion: Response to salmeterol does not vary between association between albuterol use and worsening asthma in ADRB2 genotypes after chronic dosing with an inhaled patients homozygous for arginine (Arg/Arg) at codon 16 of the b-receptor. However, it is not known whether similar responses Clinical implications: Analyses from this study indicate that occur in Arg/Arg patients receiving long-acting b2-agonists.
genetic polymorphisms leading to Arg16Gly sequence changes Objective: We sought to evaluate the effects of variation in the within the b2-adrenergic receptor do not affect patients' b2-adrenergic receptor gene (ADRB2) on clinical response to responses to recommended asthma therapy with salmeterol salmeterol administered with fluticasone propionate.
and fluticasone propionate. (J Allergy Clin Immunol Methods: Subjects (n 5 183) currently receiving short-acting b2-agonists were randomized to twice-daily therapy withsalmeterol, 50 mg, administered with fluticasone propionate, Key words: Asthma, salmeterol xinafoate, genotype, polymorphism 100 mg, in a single inhaler or daily therapy with montelukast (genetics), receptors, b2, adrenergic, fluticasone propionate 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 Genetic studies in asthma have led to advances in our receiving salmeterol, regardless of Arg16Gly genotype.
understanding of the association between gene variants Morning peak expiratory flow in subjects with the Arg/Arg and the responses to specific asthma treatments. Recent genotype showed 89.0 6 16.1 L/min improvement over baseline studies have revealed the presence of single nucleotide compared with 93.7 6 12.7 L/min for Gly/Gly subjects and polymorphisms (SNPs) within ADRB2, the gene coding 92.5 6 11.9 L/min for Arg/Gly subjects. Pairwise changes were for the b2-adrenergic receptor (b2-AR). Some ADRB2 similar for Arg/Arg compared with Gly/Gly or Arg/Gly SNPs result in changes within the amino acid sequence genotypes (estimated differences, 4.7 L/min and 3.5 L/min, of the b2-AR, leading to alterations of its properties, pos- respectively). Responses did not appear to be modified by sibly associated with various asthma-related phenotypes, haplotype pairs. During the run-out period, all subjects had including lower pulmonary function and altered broncho- predictable and similar decreases in measures of asthmacontrol, with no differences between genotypes.
dilator reversibility to short-acting b2-adrenergic Variability in response, attributed to SNPs associated withasthma severity or altered b-agonist pharmacology, mighthave important implications for asthma clinical therapyand could define subgroups of asthmatic patients with From aWake Forest University School of Medicine, Winston-Salem; and bGlaxoSmithKline, Research Triangle Park.
The b2-AR is a 413-amino-acid G protein–coupled Disclosure of potential conflict of interest: E. R. Bleecker has received grant support from Altana, AstraZeneca, Boehringer-Ingelheim, Centocor, receptor encoded for by an intronless gene (ADRB2) lo- Genentech, GlaxoSmithKline, and Novartis; has consultant arrangements cated on chromosome Variation in the activity with Aerovance, Altana, AstraZeneca, Centocor, Critical Therapeutics, of this cell-surface receptor mediates the effects of b2- Genentech, GlaxoSmithKline, and Novartis; and is on the speakers' bureau adrenergic agonists on a number of important cellular for AstraZeneca, GlaxoSmithKline, Genentech, and Merck. M. Klotsman responses.Screens of ADRB2 have revealed at least 19 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 SNPs within the coding and promoter region, some of employed by GlaxoSmithKline.
which might influence response to b2-agonists.The Received for publication December 1, 2005; revised June 25, 2006; accepted most prominent coding SNP is characterized by substitu- for publication June 27, 2006.
tion of glycine for arginine at codon 16 (Arg16Gly), which Available online August 29, 2006.
Reprint requests: Eugene R. Bleecker, MD, Pulmonary, Critical Care, Allergy occurs commonly in the general population (minor allele and Immunologic Diseases, Center for Human Genomics, Wake Forest frequency in approximately one sixth of the general University School of Medicine, Medical Center Blvd, Winston-Salem, asthma population and about one fourth of the African NC 27157. E-mail: American In vitro studies have shown that the Gly-16 receptor exhibits enhanced downregulation Ó 2006 American Academy of Allergy, Asthma and Immunologydoi:10.1016/j.jaci.2006.06.036 after b-agonist exposure, but the data remain J ALLERGY CLIN IMMUNOL 810 Bleecker et al over a 12-week period and to evaluate clinical asthma Abbreviations used stability during withdrawal of therapy.
ADRB2: b2-Adrenergic receptor gene b2-AR: b2-Adrenergic receptor BAGS: Beta-agonist Genotype Study BARGE: Beta Adrenergic Response by Genotype BUP: b-upstream peptide FSC: Fluticasone propionate/salmeterol Data from 2 identical studies, with results published in 2001 and HWE: Hardy-Weinberg equilibrium 2002, in which DNA was collected were used for these analy- ICS: Inhaled corticosteroid ses.The replicate trials were designed to evaluate the efficacy LABA: Long-acting b and safety of fluticasone propionate/salmeterol (FSC), 100/50 mg PEF: Peak expiratory flow Diskus (GlaxoSmithKline, Research Triangle Park, NC), in SABA: Short-acting b adolescent and adult subjects whose asthma was inadequately con- SLIC: Salmeterol 6 ICSs trolled with SABAs alone. Subjects were eligible for inclusion if SNP: Single nucleotide polymorphism they were 15 years of age or older and had a history of persistent SOCS: Salmeterol or Corticosteroids asthma of at least 6 months. All subjects were required to have anFEV1 of between 50% and 80% of predicted value and demonstrate15% or greater reversibility within 30 minutes after 2 puffs (180 mg)of albuterol (Ventolin; GlaxoSmithKline). Spirometry was per-formed according to the American Thoracic Society published Data analyses of clinical trials suggest that SNPs can guidelines.Before study enrollment, the aims of these clinical influence the response to both short-acting b2-agonists trials and pharmacogenetic analyses were fully explained, and in- (SABAs) and long-acting b2-agonists formed consent was obtained from each participant. The study pro- However, variations in study designs and differences in tocols were reviewed and approved by the appropriate institutional sample size have led to inconclusive results.For exam- review boards.
ple, some studies have reported no change in broncho-dilator response to either SABAsor in asthmatic subjects with varying b Eligible subjects entered a 2-week run-in period during which all 2-AR genotypes. In con- trast, results from the Beta-agonist Genotype Study participants replaced their oral or inhaled SABAs with albuterol (BAGS) reported by Israel et showed that B16-Arg/ prescribed as needed for the relief of acute asthma symptoms. PEF, Arg homozygous subjects had a small decrease in morning albuterol use, asthma symptoms, and nighttime awakenings wererecorded daily by the subjects on a diary card. After the run-in period, peak expiratory flow (PEF) when receiving regular albu- participants meeting randomization criteria (defined as the best FEV terol, but no change was observed with albuterol used of between 50% and 80% of predicted value but within 615% of the on an as-needed basis. Taylor et have extended these best predose FEV1 obtained at screening and 5 or more days requiring observations in ADRB2 variations in pulmonary function albuterol use or a diary card asthma symptom score of 2 on 3 or showing that Arg/Arg homozygous subjects receiving more days by using a 6-point scale [0 5 no symptoms, 5 5 severe albuterol had a decrease in PEF, as well as an increase in symptoms] during the previous week) entered the double-blind phase exacerbations. Interestingly, this effect was not found in of the study and were randomized to receive one of the following Arg/Arg homozygous subjects receiving salmeterol.
treatments for a 12-week period: FSC, 100/50 mg Diskus twice daily More recently, the Beta Adrenergic Response by Geno- plus placebo montelukast once daily, or oral montelukast, 10 mg once type (BARGE) study from the Asthma Clinical Research daily plus placebo Diskus twice daily. The current analyses wererestricted to those participants randomized to therapy with FSC.
Network has shown, using a prospective study design, Information on the participant's race/ethnicity, medical condition that Arg/Arg homozygous subjects have reduced peak and treatment, medical history, and family medical history was flow and associated responses over time compared with collected and recorded according to a standardized protocol. Baseline Gly/Gly homozygous In addition, a recent data for PEF, albuterol use, asthma symptoms, and nighttime retrospective analysis of 2 Asthma Clinical Research awakenings was defined as the mean value over the 7 days before Network clinical trials has shown decreased pulmo- randomization. Baseline FEV1 was defined as the randomization visit nary function with salmeterol in Arg/Arg homozygous FEV1 measurement. During the study, FEV1 was measured at treat- ment weeks 1, 4, 8, and 12 and 3 days after treatment.
The clinical implications of these findings could be significant, considering the recent shift toward the use of LABAs administered with inhaled corticosteroids Genotyping was performed in a blinded manner at a central (ICSs) to achieve asthma control in patients with persistent laboratory (GlaxoSmithKline) using collected blood samples on all asthma.This approach is recommended by global subjects for whom a sample was available. Previously characterized asthma treatment guidelines in patients who remain symp- coding SNPs in the b2-AR gene (HUGO nomenclature: ADRB2;sequence accession ID: NM_00002found in the b-upstream pep- tomatic despite low doses of an In the present tide (BUP) at nucleotide position 247 from the start codon (BUP- study we analyzed data from 2 large, identical randomized Cys/Arg) at amino acid positions 16 (Arg16Gly), 27 (Gln27Glu), trials in which genetic samples were The and 164 (Thr164Ile) were genotyped.
aims of these analyses were to evaluate the effects of var- Departures from Hardy-Weinberg equilibrium (HWE) were iation in ADRB2 on clinical response to the LABA, salme- assessed by using a x2 goodness-of-fit test. Assuming that each locus terol, administered with the ICS, fluticasone propionate, is in HWE, haplotype probabilities were estimated among white J ALLERGY CLIN IMMUNOL Bleecker et al 811 VOLUME 118, NUMBER 4 TABLE I. Localization of SNPs and identification of haplotypes of the b2-AR gene (ADRB2) among 296 white subjects Corresponding Drysdale TABLE II. Demographic and baseline characteristics of subjects by Arg16Gly genotype B16-Arg/Arg (n 5 29) B16-Arg/Gly (n 5 89) B16-Gly/Gly (n 5 65) Mean age (y [SD]) Race/ethnicity (n [%]) FEV1 % reversibility (SD) FEV1 % predicted (SD) Nighttime awakenings (SD) Albuterol use, total puffs (SD) Rescue-free days (SD) Asthma symptom scores (SD) Symptom-free days (SD) participants by using an expectations/maximization sex, race/ethnicity, FEV1 percent predicted, reversibility, and the ob- Genetic analyses were performed by using the HelixTree software served end-of-study value were conducted on the data collected dur- package (Golden Helix, Bozeman, Mont).
ing the run-out phase. In the case of FEV1, only one posttreatmentobservation was collected; an analysis of covariance was performed Statistical analysis to test for differences in FEV1 among genotypes during the run-out The primary hypothesis is that Arg/Arg homozygotes do not have phase. In addition, analyses of the effects of haplotype on clinical differing clinical responses to salmeterol in the presence of an ICS outcome were performed.
during treatment or when treatment is discontinued from subjectswith the Arg/Gly or Gly/Gly genotype.
All subjects for whom DNA was obtained were included in the analyses. The original studies were not powered to detect differences Baseline distributions among genotypes; rather, the studies were powered to detect clinicaloutcome differences between FSC and montelukast. However, we Genetic samples were available for 183 (43%) FSC performed ANOVAs to test for differences among genotypes (Arg/ recipients from the 2 identical studies. The distribution of Arg, Arg/Gly, and Gly/Gly) and haplotypes in white subjects at the BUP-Cys/Arg, Arg16Gly, Gln27Glu, and Thr164Ile baseline (). Evaluation of the effect of genotype on each clin- genotypes were all found to be in HWE. ADRB2 haplo- ical parameter (FEV1, morning PEF, albuterol use, and asthma symp- type frequencies from unphased genotypes were estimated, tom scores) during the treatment phase was carried out through the and haplotype pairs were assigned to white individuals.
use of repeated-measures analyses adjusted for age, sex, race/ethnic- Haplotype frequencies were not estimated in the other ity, baseline FEV1 percent predicted, and reversibility. SAS PROCMIXED was used to construct least-squares means, their associated ethnic groups because of the small sample size.
SEs, and CIs by week, assuming the observations were correlated There were no significant differences in baseline demo- within each subject. Similar analyses for daily values of morning graphic, clinical, and pulmonary function characteristics PEF, albuterol use, and asthma symptom scores adjusted for age, across the Arg16Gly genotypes at baseline


J ALLERGY CLIN IMMUNOL 812 Bleecker et al TABLE III. Changes from baseline in the Arg16Gly genotype at the end of 12 weeks of treatment with FSC Morning PEF (L/min) Albuterol use (puffs/d) Asthma symptom score Arg16Gly genotype FIG 1. Change from baseline in morning PEF, FEV1, albuterol use, and asthma symptom scores during the12-week treatment period and during the run-out period.
Treatment-phase response to FSC by not significant on adjustment for multiple comparisons ADRB2 genotypes and haplotypes (data not shown).
There was sustained and significant improvement (P < The clinical responses to FSC were also evaluated with .001) compared with baseline values in all measures of respect to other individual ADRB2 SNPs. Pharmacoge- asthma control in all Arg16Gly genotypes, with no differ- netic associations between response to FSC and ADRB2 ences observed across genotype subgroups and BUP-Cys/Arg, Arg16Gly, Gln27Glu, and Thr164Ile gen- ). Specifically, pairwise change from baseline in otypes and haplotype pairs were evaluated, and neither morning PEF over the 12 weeks of treatment was similar measures of pulmonary function, albuterol use, nor asthma for the Gly/Gly genotype compared with the Arg/Arg symptom scores were associated with these ADRB2 genotype (estimated difference, 4.7 L/min; P 5 .774) genotypes With the exception of the rare poly- and for the Arg/Gly genotype compared with the Arg/Arg morphism at position 164 and haplotype pairs, no discern- genotype (estimated difference, 3.5 L/min; P 5 .822; able associations were observed.
and The treatment responses to FSC for Because haplotypes might be more informative than FEV1, albuterol use, and asthma symptoms were also individual SNPs, associations between haplotype pairs similar across all genotype subgroups, and no significant and outcomes were evaluated ). Analysis was differences across genotype subgroups were observed restricted to the 4 to 5 most frequently observed haplo- The results of the montelukast treatment arm type pairs. No significant associations were identified.
comparison by genotype were similar to those observed Although it is difficult to definitively rule out a haplotype in the FSC treatment arm. All observed differences were effect because of sample size, response to regularly J ALLERGY CLIN IMMUNOL Bleecker et al 813 VOLUME 118, NUMBER 4 TABLE IV. Changes from baseline at the end of 12 weeks of treatment with FSC stratified by haplotype Morning PEF (L/min) Albuterol use (puffs/d) Asthma symptom score *Haplotype pair indicates the haploid genotype pair of each of A, B, and C alleles. For instance, AA indicates an A allele at each of the 2 gene loci on the chromosome, and AB indicates an A allele at the first locus and a B allele at the second.
 P 5 .033 for AB versus CC.
àP 5 .034 for BB versus CC.
TABLE V. Difference between the last 7 days on treatment and the run-out period stratified by genotype forsubjects previously treated with FSC B16-Arg/Arg (n 5 29) B16-Arg/Gly (n 5 89) B16-Gly/Gly (n 5 65) Morning PEF (L/min) Total albuterol use Total asthma symptom score *No differences between genotypes were noted.
scheduled use of FSC did not appear to be modified chronic b2-agonist stimulation, morning PEF response by ADRB2 haplotype pairs. Additional analyses were for each B16-Arg/Arg subject was examined individually performed by using software for analyzing haplotypes All but 2 Arg/Arg subjects had improvements over (haplo.score) for the same phenotypes, and no evidence baseline at end point in morning PEF, one of whom had for a significant association was found.
a documented exacerbation on day 71 of the study.
Exacerbations, defined as any event requiring medica- Furthermore, the responses to treatment with FSC for in- tion beyond study drug during treatment or the run-out dividual B16-Gly/Gly and B16-Gly/Arg subjects were period, were rare. One Arg/Arg subject and 1 Arg/Gly similar to those of the B16-Arg/Arg subjects (data not subject experienced an asthma exacerbation during the treatment phase; no subjects experienced exacerbationsduring the run-out phase.
The number of patients withdrawn was low and similar across groups. (in this article's OnlineRepository at www.jacionline.org) describes the disposi- The results of the current study do not indicate a tion of patients withdrawn during the studies.
differential effect of ADRB2 polymorphisms on responseto FSC therapy in subjects with asthma in this study.
Run-out phase response by genotype Prior studies suggest that the therapeutic responses to reg- After 12 weeks of treatment with FSC, treatment was ularly scheduled therapy with short-acting bronchodila- discontinued for 2 to 4 days while subjects continued to tors vary as a result of genetic polymorphisms involving use albuterol as needed and record daily symptoms and a variation at the 16th amino acid position of the b2-AR.
PEF on diary cards. Baseline for this run-out period was A recent report by Wechsler et alanalyzed data from defined as the average of the last 7 days of the FSC the Salmeterol or Corticosteroids (SOCS) and Salmeterol treatment period. During the run-out phase, no differences 6 ICSs (SLIC) trials and concluded that a subset of pa- were noted in any of the clinical responses to FSC tients in SLIC with B16-Arg/Arg (n 5 8) do not improve withdrawal across the genotypes Specifically, to the same degree as patients with B16-Gly/Gly (n 5 22) subjects had predictable and similar decreases in morning receiving salmeterol therapy, either with or without con- PEF and other measures of asthma control when switched current ICS therapy. In the SOCS trial, including patients from FSC to treatment with SABAs alone, regardless of with persistent asthma treated with salmeterol after ICS withdrawal, the B16-Arg/Arg patient subset (n 5 12)who received salmeterol alone responded significantly Specific responses by B16-Arg/Arg genotype worse than the B16-Gly/Gly subset (n 5 13), as assessed Because the B16-Arg/Arg genotype is hypothesized on the basis of changes in morning PEF, compared with to exhibit enhanced downregulation in the presence of patients who received placebo. However, in contrast to


J ALLERGY CLIN IMMUNOL 814 Bleecker et al FIG 2. Change from baseline at end point in morning PEF for individual Arg/Arg subjects (n 5 29).
the study by Wechsler et al, the findings from this study of In contrast to this study with salmeterol, a retrospective 183 subjects, perhaps the largest genetic analysis to date, analysis of BAGS results reported small decreases in show that response to the LABA salmeterol is not morning PEF over time for B16-Arg/Arg subjects (n 5 affected by the ADRB2 Arg16Gly SNP during chronic 28) who received regularly scheduled albuterol, whereas dosing in the presence of an ICS. Specifically, there similar decreases were not observed in either the Arg/Arg were sustained and quantitatively similar improvements homozygous subjects who received as-needed albuterol in lung function, symptoms, and albuterol use during or in the B16-Gly/Gly subjects (n 5 62) who received chronic treatment, regardless of Arg16Gly genotype. Al- regularly scheduled Interestingly, this study though not powered to definitively evaluate a haplotype showed a larger decrease in morning PEF after the switch effect, our haplotype analysis supports the individual from 4-times-daily albuterol to as-needed albuterol in SNP results. Drysdale et alshowed the lowest response B16-Arg/Arg but not B16-Gly/Gly subjects. Results in their 4/4 haplotype, corresponding to our BB group, from BARGE appear similar to those from BAGS for with a total of 14 subjects as opposed to the 25 in our anal- B16-Arg/Arg subjects receiving regularly scheduled albu- ysis (). Although we did not measure all 13 pos- terol, in that there was a differential response between the sible SNPs, using the SNPs at position 247, 46, 79, and 2 homozygote groups on regular b-agonist therapy, with 491, we were able to evaluate the most frequent haplo- the Gly/Gly homozygotes showing improvement in PEF types corresponding to those previously reported.
and other parameters of asthma control.
The results of this study are consistent with the findings The results of the current study evaluating therapeutic of Taylor et who examined retrospectively the rela- responses to salmeterol in patients receiving concomitant tionship between the frequency of asthma exacerbations corticosteroids do not support an effect of ADRB2 poly- and genetic variation at codon 16 of ADRB2 in subjects morphisms. The contrasting results between BAGS, receiving placebo, 4-times-daily albuterol, or twice-daily BARGE, the retrospective analysis of SOCS and SLIC, salmeterol for 24 weeks. These investigators demon- and this study can be attributed to various factors, includ- strated that although subjects treated with 4-times-daily al- ing sample size, differences in study design, asthma sever- buterol had a higher number of exacerbations compared ity, intrinsic activity of the b-agonist evaluated, and with those receiving placebo, subjects treated with salme- concomitant use of an ICS.
terol had the lowest number of exacerbations. In addition, Compounds with lower intrinsic activity are generally there was no differential response in exacerbations or believed to result in a lower potential to induce receptor lung function in subjects receiving salmeterol, regardless downregulation, a proposed mechanism of reduced of genotype. Furthermore, a retrospective study by Klots- response to b-agonists.High intrinsic activity might man et alshowed that the serial 12-hour FEV1 response also lead to an opposite response in which response to to salmeterol after 12 weeks of treatment was similar in cholinergic tone is enhanced.Salmeterol has the lowest subjects treated with salmeterol, regardless of concomitant intrinsic activity of the currently available b-agonist ICS use or Arg16Gly genotype. The current analysis did not evaluate salmeterol as monotherapy, which is not rec- Because ADRB2 is a small gene with significant linkage ommended in current asthma guidelines and could have disequilibrium across the 59 promoter and 39 untranslated contributed to the failure to detect a polymorphic effect region, functional polymorphisms in partial linkage dis- of ADRB2 on treatment response.
equilibrium with the Arg16Gly SNP might also be the J ALLERGY CLIN IMMUNOL Bleecker et al 815 VOLUME 118, NUMBER 4 cause of the divergent results in the literature because the present study that there were no associations between these would not be equally expressed in trials with small genotypes and the treatment responses to FSC or the sample sizes.
response to albuterol alone during FSC washout does not Previous studies have proposed that some patients eliminate a genetic interaction. In this regard ADRB2 might experience poorer asthma control and adverse side haplotypes have been described and reported to occur at effects associated with regular use of the potent SABA different frequencies based on The haplotype Because of these results, regular therapy analysis in this study did not reveal any significant influ- was compared with as-needed use of SABAs and shown ence on response, but the sample size, the selection criteria to have no adverse effects, but regular SABA use provided of the study population, and the lack of ethnic representa- no additional therapeutic benefits. Recent pharmacoge- tion limits these conclusions.
netic data raise questions as to whether there might be a In summary, this study evaluating associations between subset of subjects, based on b2-AR genotype, who might the polymorphic gene encoding for the b-agonist drug not respond well to chronic SABA therapy. The results of target and responses to therapy with a long-acting b- the present study suggest that this is not the case for sal- agonist showed that response to salmeterol does not vary meterol when administered with an ICS and that current by ADRB2 genotypes or haplotypes during chronic dosing treatment guidelines are appropriate for a broad popu- in the presence of an ICS. However, larger, prospective, lation of asthmatic subjects, including those with b2-AR clinical pharmacogenetic studies with higher power to evaluate haplotypes across different ethnic/racial groups, Both clinical trials and observational studies support as well as genetic epidemiologic studies, are clearly the therapeutic value of inhaled LABAs in combination needed to help elucidate this field of great interest.
with ICSs. Specifically, if b-agonist use were associatedwith deleterious outcomes in an at-risk genetic subgroup We thank Laura Sutton, PharmD, for her assistance in preparing reported to occur in a small but significant percentage the manuscript and Deborah Meyers, PhD, for her assistance with of the asthma population (eg, the B16-Arg/Arg genotype the haplotype analyses.
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Amorphization of Pharmaceuticals by Co- grinding with Neusilin® Amorphization of crystalline drugs can be achieved In a previous report, we discussed solid dispersion through several methods. The most common method methods using Neusilin as an adsorption carrier to is melting and solidifi cation by rapid cooling over liquid improve dissolution and bioavailabilty of poorly water

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