ADRB2 Polymorphisms and Budesonide/Formoterol Responses in COPD

doi:10.1378/chest.11-1655

Chest

Volume 142, Issue 2, August 2012, Pages 320-328

https://doi.org/10.1378/chest.11-1655 Get rights and content

Background

Effects of β₂-adrenergic receptor gene (ADRB2) polymorphism on therapeutic responses to long-acting β₂-adrenergic agonists have not been evaluated in long-term COPD trials. We aimed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD.

Methods

Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I (NCT00206167) or the 6-month trial II (NCT00206154) were randomly assigned to bid budesonide/formoterol pressurized metered-dose inhaler (pMDI) 320/9 μg or 160/9 μg, budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg (trial II), budesonide pMDI 320 μg (trial II), formoterol dry powder inhaler 9 μg, or placebo. The effect of Gly16Arg on predose FEV₁ and 1-h postdose FEV₁, exacerbations, diary variables, and adverse events were analyzed.

Results

No significant interaction between genotype and treatment response was observed for predose (P ≥ .197) or postdose FEV₁ (P ≥ .125) in either pharmacogenetic study (n = 2,866). The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups (both studies). Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment.

Conclusion

Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD.

Trial registry

ClinicalTrials.gov; Nos.: NCT00206167, NCT00206154; URL: clinicaltrials.gov.

Section snippets

Study Design

Methodology for these trials in patients with moderate to very severe COPD has been reported previously.18, 19 A specific consent was used to obtain blood samples for pharmacogenetic analysis. Institutional review board or independent ethics committee ethical approval for the pharmacogenetic component was obtained at each site.

Study I was 12 months (NCT00206167¹⁸); genotype results from the 6-month study II (NCT00206154¹⁹) served to replicate the genotype findings from study I. Eligible

Patients

DNA samples were obtained from 1,490 of 1,964 randomized patients (75.9%) in trial I and 1,393 of 1,704 randomized patients (81.7%) in trial II (Fig 1). Demographic and baseline clinical characteristics are presented in Table 1. Patients had moderate to very severe COPD, with a mean FEV₁ of 1.05 L. The percentages of patients who met ATS criteria for bronchodilator reversibility were similar across Gly16Arg genotype groups (29%-39%) in both studies. There were no differences in baseline

Discussion

Results from this pharmacogenetic research showed no effect of Gly16Arg genotype on the efficacy or tolerability of LABA therapy with formoterol, either alone or in combination with budesonide, in COPD. Improvements from baseline to the treatment average in pulmonary function, exacerbation frequency, dyspnea score, SGRQ total score (in study II), and diary variables were similar across genotype groups. Clinical trial I was designed with sufficient power to detect a treatment effect on

Acknowledgments

Author contributions: Dr Martin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects.

Dr Bleecker: contributed substantially to analysis and interpretation of the data, drafted portions of the article, revised it critically for important intellectual content, and approved the final version for publication.

Dr Meyers: contributed substantially to analysis and

References (31)

E Israel et al.
Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial
Lancet
(2004)
ER Bleecker et al.
Effect of ADRB2 polymorphisms on response to long-acting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies
Lancet
(2007)
ME Wechsler et al.
Effect of beta2-adrenergic receptor polymorphism on response to long-acting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomised, placebo-controlled, crossover trial
Lancet
(2009)
N Hizawa
Genetic backgrounds of asthma and COPD
Allergol Int
(2009)
BR Celli et al.
Bronchodilator responsiveness and onset of effect with budesonide/formoterol pMDI in COPD
Respir Med
(2011)
N Hizawa et al.
Beta2-adrenergic receptor genetic polymorphisms and short-term bronchodilator responses in patients with COPD
Chest
(2007)
WJ Kim et al.
Genetic association analysis of COPD candidate genes with bronchodilator responsiveness
Respir Med
(2009)
NK Leidy et al.
Evaluating symptoms in chronic obstructive pulmonary disease: validation of the Breathlessness, Cough and Sputum Scale
Respir Med
(2003)
ER Bleecker et al.
Salmeterol response is not affected by beta2-adrenergic receptor genotype in subjects with persistent asthma
J Allergy Clin Immunol
(2006)
N Hizawa
Pharmacogenetics of β2-agonists
Allergol Int
(2011)

HS Nelson et al.

The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol [published correction appears in Chest. 2006;129(5):1393]

Chest

(2006)

M Mann et al.

Serious asthma exacerbations in asthmatics treated with high-dose formoterol

Chest

(2003)

G Bensch et al.

One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma

Ann Allergy Asthma Immunol

(2002)

MC Matheson et al.

Beta2-adrenergic receptor polymorphisms are associated with asthma and COPD in adults

J Hum Genet

(2006)

E Israel et al.

The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma

Am J Respir Crit Care Med

(2000)

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Association between ADRB2, IL33, and IL2RB gene polymorphisms and lung cancer risk in a Chinese Han population
2019, International Immunopharmacology
Citation Excerpt :
ADRB2 encodes the β2-adrenergic receptor, which plays a biological function in muscle relaxation in the lungs [24]. Previous studies have reported that ADRB2 gene variants may influence the severity of cystic fibrosis (CF) and lead to different responses to bronchodilators in CF patients and budesonide/formoterol in COPD patients [25,26]. Rs1042711 is located in the 5′ upstream region of ADRB2, and is a non-synonymous mutation (Arg19Cys) [27].
This study aimed to explore the associations between polymorphisms of a very important pharmacogene, ADRB2, two inflammation-related genes, IL33 and IL2RB, and the risk of lung cancer.
Six polymorphisms of ADRB2, IL33, and IL2RB were genotyped in 300 lung cancer patients and 300 healthy controls using MassARRAY. The relationship between genotypes and lung cancer risk was evaluated using chi-square tests.
The minor allele of rs1042711 was a risk allele for lung cancer, whereas the minor alleles of rs7025417 and rs5756523 had protective effects against lung cancer (p＜0.05). The CT genotype of rs1042711 and the GT genotype of rs1560642 were associated with increased risk of lung cancer, whereas the CC and AA genotypes of rs7025417 and the CT and CC genotypes of rs5756523 were associated with decreased disease risk (p < 0.05). Genetic model analysis shows that rs1042711 and rs1560642 were associated with increased risk of lung cancer; whereas rs7025417, rs5756523, and rs2284033 were associated with decreased disease risk (p < 0.05). Stratification analysis showed that rs1042711 and rs1560642 were associated with increased risk of lung cancer in nonsmokers and smokers, respectively, whereas rs7025417 and rs5756523 were associated with decreased disease risk in both subgroups (p＜0.05).
Our results shed new light on the association between polymorphisms of ADRB2, IL33, and IL2RB and the risk of lung cancer.
Beta-2-adrenoreceptor polymorphism at position 16 determines the clinical severity of chronic obstructive pulmonary disease
2017, Pulmonary Pharmacology and Therapeutics
The Arg/Arg homozygosity at codon 16 of the beta-2-adrenoreceptor (ADRB2) gene has been thought to predispose asthma patients to a poorer therapeutic response to beta-2-mimetics, or to worse control of the disease. In contrast, the results of the studies analysing the effect of ADRB2 polymorphisms on the response to beta-2-adrenoreceptor agonists in chronic obstructive pulmonary disease (COPD) patients are sparse and inconclusive. The aim of this research was to verify if p.Arg16Gly (c.46A > G) and p.Gly27Glu (c.79G > C) single nucleotide polymorphisms (SNPs) exert a negative effect on the selected clinical indicators of COPD.
The SNPs of the ADRB2 were identified by multiplex allele-specific PCR on DNA isolated from the venous blood leukocytes of 92 patients with stable grade COPD. In addition, all of the patients were asked about the course of COPD during the 12 months preceding the study, including the frequency of exacerbations requiring hospitalisation, the number of antibiotic therapy courses given due to the lower respiratory tract infection, and the number of courses of systemic corticosteroid therapy administered due to the exacerbation of COPD.
Arg/Arg homozygotes at codon 16 required at least two courses of antibiotic therapy administered as a result of a lower respiratory tract infection significantly more frequently than carriers of other polymorphic variants of the ADRB2. Moreover, they were the only ones who required three or more courses of corticosteroid therapy due to COPD exacerbation. No significant relationships were observed between the polymorphism at codon 27 and the analysed clinical indicators of COPD severity.
These data suggested that Arg/Arg homozygosity at codon 16 of the ADRB2 gene predisposes patients to a clinically more severe course of COPD.
Asthma
2017, Genomic and Precision Medicine: Primary Care: Third Edition
Asthma is a complex disease affecting over 300 million individuals in the developed world. Most asthma cases, including in adults, have their origins in childhood. Asthma is a clinical syndrome characterized by reversible episodes of airflow obstruction, airway hyperresponsiveness, and a chronic inflammatory process of the airways of which many different cells play a role. Modern estimates of heritability of asthma due to additive genetic effects from common variants are between 61.5%=/−16%. Candidate gene and genome-wide association studies have identified over 30 reproducible loci associated with the disease. Gene expression profiling of asthma in blood and bronchial epithelium implicates highly relevant biology related to systemic inflammation. Despite the availability of several classes of therapeutic agents for asthma, it has been estimated that as many as one half of all patients do not respond to treatment with b2 agonists, leukotriene antagonists, or inhaled corticosteroids. Over 20 reproducible genetic loci have been identified for these three treatment pathways. Asthma genomics is in its early stages and has the potential to have a great clinical impact in the next 5–10 years through the development of genomic predictors of disease occurrence, response to asthma medication, and exacerbations.
Genetic effects on treatment response of umeclidinium/vilanterol in chronic obstructive pulmonary disease
2016, Respiratory Medicine
Treatment with long-acting β₂-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) for chronic obstructive pulmonary disease (COPD) is standard, but response varies. We investigated genetic association with treatment response to umeclidinium (UMEC, a LAMA), vilanterol (VI, a LABA), and combination therapy.
Data from 17 clinical trials (N = 6075) in patients with COPD receiving once-daily UMEC/VI (125/25mcg or 62.5/25mcg), UMEC (125 or 62.5mcg), VI (25mcg) or placebo were used. Genetic association with change from baseline in trough forced expiratory volume in 1 s (FEV₁) ∼24 h post-dosing was assessed for: (i) 3 β₂-adrenoceptor (ADRB2) gene variants; (ii) 298 single-nucleotide polymorphisms (SNPs) with prior evidence of associations; (iii) human leukocyte antigen (HLA) alleles and (iv) genome-wide association study (GWAS) SNPs. Other endpoints were (i) reversibility at screening; and at baseline: (ii) FEV₁; (iii) forced vital capacity (FVC), and (iv) FEV₁/FVC ratio. Using linear regression, the inverse normal transformed residuals were pooled together, first across treatment group, then across studies for each monotherapy, then combination therapy and finally for every treated patient.
Of 6075 patients, 1849 received UMEC/VI, 1390 received UMEC, 1795 received VI, and 1041 received placebo. None of the ADRB2 variants, HLA alleles or GWAS variants tested were associated with treatment response or baseline endpoints. Four SNPs in FAM13A (rs7671167, rs2869967, rs1964516, rs1903003) were significantly associated with baseline FEV₁/FVC ratio (p < 3 × 10⁻⁵) after adjusting for multiple testing.
No genetic association was found with treatment response to UMEC or VI when administered as monotherapies or in combination.
Genetics in Asthma and COPD
2015, Murray and Nadel's Textbook of Respiratory Medicine: Volume 1,2, Sixth Edition
Pharmacogenetics of COPD: A role for the β<inf>2</inf>-adrenergic receptor gene?
2014, The Lancet Respiratory Medicine

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Funding/Support: This work was supported by AstraZeneca LP. Drs Bleecker and Meyers were partially supported by the National Institutes of Health [Grant HL 056899].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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Chest

Original ResearchCOPDADRB2 Polymorphisms and Budesonide/Formoterol Responses in COPD

Background

Methods

Results

Conclusion

Trial registry

Section snippets

Study Design

Patients

Discussion

Acknowledgments

Lancet

Lancet

Lancet

Allergol Int

Respir Med

Chest

Respir Med

Respir Med

J Allergy Clin Immunol

Allergol Int

Chest

Chest

Ann Allergy Asthma Immunol

Beta2-adrenergic receptor polymorphisms are associated with asthma and COPD in adults

J Hum Genet

The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma

Am J Respir Crit Care Med

Original Research
COPD
ADRB2 Polymorphisms and Budesonide/Formoterol Responses in COPD