COPD

Lung Function Response to 12-week Treatment with CombinedInhalation of Long-acting b2 Agonist and GlucocorticoidAccording to ADRB2 Polymorphism in Patients with ChronicObstructive Pulmonary Disease

Woo Jin Kim Æ Yeon-Mok Oh Æ Joohon Sung Æ Tae-Hyung Kim Æ Jin Won Huh ÆHoon Jung Æ Ji-Hyun Lee Æ Eun-Kyung Kim Æ Jin Hwa Lee Æ Sang-Min Lee ÆSangyeub Lee Æ Seong Yong Lim Æ Tae Rim Shin Æ Ho Il Yoon Æ Sung-Youn Kwon ÆSang Do Lee

Received: 4 January 2008 / Accepted: 5 June 2008 / Published online: 29 August 2008

� Springer Science+Business Media, LLC 2008

Abstract Recent reports suggest that b2-adrenergic

receptor (ADRB2) genotypes are associated with thera-

peutic responses to b2 agonists in asthmatics. However,

few studies have investigated therapeutic responses to b2

agonists in chronic obstructive pulmonary disease (COPD)

patients. This study investigated immediate bronchodilator

response and lung function responses following a 12-week

treatment with a long-acting b2 agonist combined with a

steroid inhaler in patients with COPD with various ADRB2

genotypes. One hundred four patients with chronic

obstruction were genotyped for codon 16 and 27 poly-

morphisms of the ADRB2 gene. The immediate

Woo Jin Kim and Yeon-Mok Oh contributed equally to this work.

W. J. Kim

Department of Internal Medicine, College of Medicine,

Kangwon National University, Chuncheon, South Korea

Y.-M. Oh � S. D. Lee (&)

Division of Pulmonary and Critical Care Medicine, Department

of Internal Medicine, and Clinical Research Center for Chronic

Obstructive Airway Diseases, Asan Medical Center, University

of Ulsan College of Medicine, 388-1 Pungnap-dong, Sonpa-gu,

Seoul 138-736, South Korea

e-mail: sdlee@amc.seoul.kr

J. Sung

Department of Cancer Prevention and Epidemiology,

National Cancer Center, Goyang, South Korea

T.-H. Kim

Division of Pulmonology, Department of Internal Medicine,

Hanyang University Guri Hospital, Hanyang University College

of Medicine, Guri, South Korea

J. W. Huh � H. Jung

Department of Internal Medicine, Ilsan Paik Hospital,

Inje University, Goyang, South Korea

J.-H. Lee � E.-K. Kim

Division of Pulmonary and Critical Care Medicine, Department

of Internal Medicine, Bundang CHA Hospital, College

of Medicine, Pochon CHA University, Seongnam, South Korea

J. H. Lee

Department of Internal Medicine, Ewha Womans University

Mokdong Hospital, College of Medicine, Ewha Womans

University, Seoul, South Korea

S.-M. Lee

Division of Pulmonary and Critical Care Medicine, Department

of Internal Medicine, Clinical Research Institute, Seoul National

University Hospital, Lung Institute, Medical Research Center,

Seoul National University College of Medicine, Seoul,

South Korea

S. Lee

Division of Respiratory and Critical Care Medicine, Department

of Internal Medicine, College of Medicine, Korea University

Anam Hospital, Seoul, South Korea

S. Y. Lim

Division of Pulmonary and Critical Care Medicine, Department

of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan

University School of Medicine, Seoul, South Korea

T. R. Shin

Department of Internal Medicine, Kangnam Sacred Heart

Hospital, Hallym University College of Medicine, Seoul,

South Korea

H. I. Yoon � S.-Y. Kwon

Respiratory Center, Seoul National University Bundang

Hospital, Department of Internal Medicine, Seoul National

University College of Medicine, Seongnam, South Korea

123

Lung (2008) 186:381–386

DOI 10.1007/s00408-008-9103-9

bronchodilator response to b2-agonist treatment was eval-

uated after inhalation of 400 lg salbutamol. In addition,

long-term response was evaluated using observed change

in spirometric values before and after the treatment with

salmeterol (50 lg) combined with fluticasone propionate

(500 lg) inhalation twice daily for 12 weeks. In terms of

codon 16 variants, the immediate bronchodilator response

to salbutamol was 6.4 ± 0.8% (% predicted value) in

Arg/Arg patients, 4.9 ± 0.7% in Arg/Gly patients, and

5.8 ± 1.2% in Gly/Gly patients (p = 0.418). The FEV1

changes following the 12-week treatment were 7.0 ± 1.2%

in Arg/Arg patients, 3.0 ± 1.5% in Arg/Gly patients, and

7.2 ± 1.2% in Gly/Gly patients (p = 0.229). Similarly,

there was no difference between codon 27 variants in terms

of immediate bronchodilator response or FEV1 changes

after 12 weeks of treatment. We were unable to demon-

strate an association between ADRB2 genotype and the

effect on lung function of 12-week treatment with com-

bined long-acting b2 agonist and glucocorticoid inhalation

or on the immediate bronchodilator response to a short-

acting b2 agonist in patients with COPD.

Keywords b-agonist � COPD � Polymorphism

Introduction

b2-adrenergic agonists are frequently used in patients with

chronic obstructive pulmonary disease (COPD) and

asthma. The b2-adrenergic receptor is the target molecule

of b2 agonists. The gene encoding the b2-adrenergic

receptor, ADRB2, is located on chromosome 5q31.32, and

the presence of single nucleotide polymorphisms (SNP) in

this gene has been reported. The two nonsynonymous SNPs

in the ADRB2 gene at positions 16 and 27 have been well

characterized [1].

Previous studies revealed that the polymorphisms did

not confer differences in terms of b2-agonist pharmacoki-

netic responses [2]. However, both asthmatic and

nonasthmatic American [3] and Korean [4] children with

the Arg-16 variant show a greater response to short-acting

b2 agonists. A recent study of mild asthmatics reported that

position 16 Arg/Arg homozygous subjects had decreased

lung function with regular long-term use of short-acting b2

agonists compared with Gly/Gly homozygous subjects

[5, 6]. However, another study reported there was no

association between genotype and response to b2-agonist

therapy [7]. Studies on pulmonary function responses

associated with long-acting b2 agonists with or without

steroid inhalation in asthmatics have reported conflicting

findings [8, 9]. Combined inhalation of a long-acting b2

agonist and glucocorticoid leads to lung function

improvement in COPD patients [10–12], and there may

be differences in b-agonist responses according to the

genetic constitution of asthma patients. However, there is

insufficient information regarding genotype-specific bron-

chodilator responses in patients with COPD.

The present study investigated whether ADRB2 geno-

type differences in patients with chronic obstruction

affected responses to immediate bronchodilator treatment

and responses to long-acting b2 agonist combined with

steroid inhaler treatment.

Methods

Subjects

The study examined data extracted from the Korean

Obstructive Lung Disease (KOLD) Cohort, which com-

prises patients with COPD or asthma. Those patients were

recruited from pulmonary clinics in 11 hospitals in South

Korea. The KOLD Cohort was designed primarily to

develop a systematic diagnostic model and an integrative

prognostic factor of obstructive lung diseases. In the

KOLD Cohort, 147 patients were enrolled from June 2005

to August 2006, and a total of 800 patients are expected to

be enrolled by 2012 if we assume the same pace of

recruitment. For each patient, computed tomographic

scans, blood, urine, pulmonary function, exercise capacity,

and clinical information including quality of life were

obtained. Written informed consent was obtained from all

subjects and the protocols were reviewed and approved by

Institutional Review Boards of all participating hospitals.

In this study, COPD was defined when all of the fol-

lowing criteria were met: (1) less than 0.7 for post-

bronchodilator FEV1/FVC (forced expiratory volume in

one second/forced vital capacity), (2) more than ten pack-

years of smoking history, and (3) no or minimal abnor-

mality on chest radiographs.

Genotyping

ADRB2 genotyping was performed on all patients. Geno-

mic DNA was prepared from blood for genotype analysis.

Genotypes of codons 16 and 27 were determined using

polymerase chain reaction (PCR) and restriction fragment

length polymorphism (RFLP) techniques as previously

described [3]. Restriction digests were electrophoresed on

4% agarose gels and visualized using ethidium bromide.

Spirometry and Bronchodilator Response

For all 104 patients with COPD, spirometry was performed

as recommended by the American Thoracic Society [13]

(2130 or Vmax 22, SensorMedics, CA, USA; PFDX,

382 Lung (2008) 186:381–386

123

MedGraphics, MN, USA; Master Lab 4, Jaeger, Germany).

Bronchodilator response tests were performed on all 104

patients using repeated spirometry 15 min after inhalation

of 400 lg salbutamol with a spacer.

Long-term Response to 12-week Treatment

with Inhalation of Long-acting b2 Agonist

and Glucocorticoid

For all patients, long-term response was evaluated using

observed change in spirometric values before and after the

treatment with salmeterol (50 lg) combined with flutica-

sone propionate (500 lg) dry-powder inhalation twice daily

for 12 weeks. The use of respiratory medicine was

restricted for 2 weeks before enrollment. The patients were

instructed that the inhalation was to be performed twice a

day, one inhalation early in the morning and the other in

the evening. The spirometry after 12 weeks of treatment

was measured and the difference in FEV1 before and after

treatment was determined and expressed as the percentage

of FEV1 change to predicted value. Compliance to inhaler

use and smoking status was monitored by a trained nurse at

every visit. The subjects were asked to bring back their

inhalation device in order to count how much was used.

Their obligatory visits were at day 1 and after 12 weeks,

but they usually visited once or twice more during the first

12 weeks.

Statistical Analysis

Analysis of variance (ANOVA) was used to analyze the

bronchodilator response to determine any differences

between genotypes. Significant ANOVA findings resulted

in post hoc mean tests. The association between longitu-

dinal lung function changes and ADBR2 genotype was

examined adjusting for age, sex, smoking status, and

baseline FEV1. After testing for normality, a random effect

model was used where hospital characteristics and the

individual compliance with drug therapy were modeled as

random errors [14] (mixed procedure of SAS for Windows

v9.2). Association between haplotypes and lung function

changes was tested using haplo.stats [15].

Results

Baseline Characteristics

Of the 145 KOLD Cohort patients, 116 patients met all cri-

teria for chronic obstruction. Twelve patients withdrew

consent, leaving 104 patients to be analyzed. There were no

significant differences in baseline demographics and base-

line FEV1 across the Arg16Gly and the Gln27Glu (Table 1).

Bronchodilator Responsiveness According to Genotype

In terms of codon 16 polymorphisms, the immediate bron-

chodilator response to salbutamol was 6.4 ± 0.8% (%

predicted value, mean ± standard error [SD]) in Arg/Arg

genotype patients, 4.9 ± 0.7% in Arg/Gly patients, and

5.8 ± 1.2% in Gly/Gly patients. These responses were not

found to be statistically different (p = 0.656, unadjusted;

p = 0.773, adjusted; p = 0.418, mixed model) (Fig. 1). The

bronchodilator responses were also similar for different

codon 27 polymorphisms: 5.8 ± 0.5% for Gln/Gln patients,

5.6 ± 1.3% for Gln/Glu patients, and -5.6% for Glu/Glu

patients (p = 0.838, unadjusted; p = 0.670, adjusted;

p = 0.072, mixed model) (Fig. 1). Haplotype analysis using

haplo.stats revealed no association between haplotypes in

ADRB2 and bronchodilator responsiveness (Table 2).

Response after the 12-week Treatment According to

Genotype

The mean FEV1 increase across all patients after 12 weeks

was 168 ± 26 ml. Compliance was checked completely

for 100 of 104 patients. The overall drug compliance sur-

vey revealed that 71 (71%) of the 100 patients used the

inhaler more than 80%. The greater than 80% compliancy

breakdown across genotypes was 70% (26/37) for the Arg/

Arg group, 75% (30/40) for the Arg/Gly group, and 65%

(15/23) for the Gly/Gly group. In terms of the Gln27Glu

genotypes, it was 78% (23/80) for Gln/Gln group, 68% (13/

19) for the Gln/Glu group, and 100% (1/1) for the Glu/Glu

group. Thirty-eight patients (37%) continued smoking

during the 12 weeks.

Table 1 Baseline characteristics according to ADRB2 genotype

Codon 16 Codon 27

Genotype Arg/Arg Arg/Gly Gly/Gly Gln/Gln Gln/Glu Glu/Glu

Number of subjects 38 42 24 83 20 1

Sex (male/female) 37/1 41/1 23/1 81/2 19/1 1/0

Age (years) 64.6 ± 1.2 65.6 ± 1.3 66.4 ± 1.3 64.9 ± 0.8 67.81 ± 1.5 62

Baseline FEV1 (L) 1.41 ± 0.10 1.49 ± 0.08 1.47 ± 0.10 1.47 ± 0.06 1.40 ± 0.11 1.31

Lung (2008) 186:381–386 383

123

In terms of the Arg16Gly genotypes, FEV1 changes

from baseline following the 12-week salmeterol/flutica-

sone propionate inhalation treatment were 221.8 ± 41.7

ml or 7.0 ± 1.2% (% predicted value) in the Arg/Arg

genotype, 89.3 ± 46.1 ml or 3.0 ± 1.5% in the Arg/Gly

group, and 224.6 ± 37.1 ml or 7.2 ± 1.2% in the

Gly/Gly group (Fig. 2). These FEV1 changes were not

found to be significantly different (p = 0.767). The result

was not changed by adjusting for smoking and FEV1

(p = 0.751), and not changed by the random effect

model (p = 0.229). Similarly, FEV1 changes did not

significantly differ between codon 27 genotypes, being

182.9 ± 25.4 ml or 5.8 ± 0.5% for Gln/Gln, 97.0 ±

84.5 ml or 3.3 ± 2.7% for Gln/Glu, and 450.0 ml or

14.9% for Glu/Glu (p = 0.515, unadjusted; p = 0.465,

adjusted; p = 0.240, random effect model). Haplotype

analysis using haplo.stats revealed no association

between haplotypes in ADRB2 and FEV1 change at

12 weeks (Table 2).

Discussion

The present study found that bronchodilator responses to a

short-acting b2 agonist and reversibility after a 12-week

treatment with combined long-acting b2 agonist and glu-

cocorticoid inhalation did not differ according to ADRB2

genotypes in patients with COPD. One recent article

reported that ADRB2 genotypes in COPD patients were

associated with short-term bronchodilator responses [16];

however, this study showed no association between

ADRB2 genotypes and bronchodilator responsiveness in

Korean COPD subjects.

The present finding of no deleterious effects of long-

acting b2 agonists in Arg homozygotes appears to be

inconsistent with some previous reports [5, 6, 8]. Those

studies concluded that regular use of a short-acting b2

agonist or a long-acting b2 agonist may produce deleterious

effects in asthmatic patients with the Arg homozygote

genotype. In terms of function, in vitro studies with

fibroblasts and airway smooth muscle cells showed that the

Gly16 allele was associated with enhanced agonist-medi-

ated receptor downregulation [17, 18]. However, more

recent studies in vitro using lung mast cells [19] and an in

vivo study [20, 21] reported that Gly16 was associated with

resistance to desensitization.

There are some possible explanations for the apparent

inconsistency between our findings and those of others.

First, steroid combined with a long-acting b2 agonist might

eliminate the deleterious effects in the Arg/Arg genotype,

as has been suggested by previous studies [5, 6, 8]. Inhaled

corticosteroids can reverse bronchodilator desensitization

Fig. 1 Bronchodilator response according to ADRB2 codon 16 and

27 genotypes. Changes in FEV1 are expressed as % predicted value

(mean ± SE)

Table 2 Haplotype analysis in ADRB2 using haplo.stats

Position

16

Position

27

Haplotype

frequency

p value for

bronchodilator

responsiveness

p value for

12-week

response

Arg Gln 0.56 0.61 0.80

Gly Gln 0.33 0.95 0.95

Gly Glu 0.10 0.29 0.63

ADRB2 haplotypes were not associated with bronchodilator respon-

siveness and 12-week response to long-acting b2-agonist

Fig. 2 Reversibility after 12-week treatment according to ADRB2genotype. Changes in FEV1 after 12 weeks from baseline are

expressed as % predicted value (mean ± SE)

384 Lung (2008) 186:381–386

123

induced by b2 agonists [22] and demonstrate synergic

pharmacodynamic effects with b2 agonists [23]. We used a

long-acting b2 agonist and steroid inhalation combination

in the current study; this combination may decrease

desensitization. Consistent with our findings, a recent study

that used a long-acting agonist combined with corticoste-

roid in asthmatics did not show desensitization in the Arg

group [9, 24].

A second explanation might be that our subjects were

COPD patients. Response or desensitization to a b2 agonist

may be different from that of asthmatics.

Third, racial differences can result in pharmacogenetic

differences in responses to b2 agonists [25]. The frequen-

cies of SNPs and haplotypes in the ADRB2 genotype in

Japanese differed from Caucasians and African-Americans

[26]. Linkage disequilibrium may be different in Asians

and some unknown important genetic variant might play a

major role [27]. The Glu27 genotype is reported to show

enhanced response and is associated with enhanced pro-

moter expression [28]. Glu27 frequencies are very low in

Japan [26] and Korea [4], and almost all persons who are

homozygous for Glu27 are homozygous for Gly16 [20].

The Gly16/Glu27 allele, which is more prevalent in Cau-

casians, might explain the asthma study result that showed

that Gly16 patients had a greater response to long-term b2

agonists.

Our study has two limitations. First, the number of

patients was not large enough to reach an appropriate

power statistically. The estimated number of patients nee-

ded to achieve the power of 0.80 is 76 per group, assuming

that the difference of 5% change in FEV1 (% predicted)

would be clinically significant. We authors report our

results as a preliminary, negative study. With the growing

recruitment for the KOLD Cohort, we hope to reach the

necessary number of cases in the future to be able to rule

out formally the genetic association. A second limitation is

related to the fact that the response to treatment with a

long-acting b2 agonist could not be assessed with exactly

the same time interval between measurements and the last

inhalation of the drug. Thus, the time interval might rep-

resent a confounding variable, although we used long-

acting inhalation drugs.

In conclusion, the ADRB2 genotype had no effect on

reversibility after a 12-week treatment with combined

long-acting b2 agonist and glucocorticoid inhalation or on

bronchodilator response after short-acting b2-agonist

treatment in patients with COPD. Of note, there were no

apparent deleterious effects of long-acting b2-agonist

treatment in Arg homozygotes when combined with glu-

cocorticoid. However, because of the relatively small

sample size, the lack of association needs to be confirmed

with a larger number of patients. The present study indi-

cates that further studies are warranted to increase the

understanding of pharmacogenetic issues relating to

ADRB2 genotypes, and to better understand the relation-

ship between the genotype and COPD susceptibility or

phenotype.

Acknowledgments This study was supported by a grant (A040153)

from the Korean Health 21 R&D Project, Ministry of Health &

Welfare, Republic of Korea, and by the pharmaceutical companies

GlaxoSmithKline Korea and AstraZeneca Korea.

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