Respiratory Medicine (2009) 103, 98e103

available at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/rmed

CT scanning-based phenotypes vary with ADRB2

polymorphisms in chronic obstructive pulmonary
disease
Woo Jin Kim a,o, Yeon-Mok Oh b,o, Joohon Sung c, Young Kyung Lee d,
Joon Beom Seo e, NamKug Kim e, Tae-Hyung Kim f, Jin Won Huh g,
Ji-Hyun Lee h, Eun-Kyung Kim h, Jin Hwa Lee i, Sang-Min Lee j,
Sangyeub Lee k, Seong Yong Lim l, Tae Rim Shin m, Ho Il Yoon n,
Sung-Youn Kwon n, Sang Do Lee b,*

a
Department of Internal Medicine, College of Medicine, Kangwon National University, Chuncheon, South Korea
b
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,
Seoul, South Korea
c
Department of Cancer Prevention and Epidemiology, National Cancer Center, South Korea
d
Department of Radiology, Bundang CHA Hospital, University of Pocheon Jungmoon College of Medicine, Seongnam,
South Korea
e
Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Research Institute of Radiology,
Seoul, South Korea
f
Division of Pulmonology, Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College
of Medicine, Guri, South Korea
g
Department of Internal Medicine, Ilsan Paik Hospital, Inje University, Goyang, South Korea
h
Department of Internal Medicine, Bundang CHA Hospital, University of Pocheon Jungmoon College of Medicine,
Seongnam, South Korea
i
Department of Internal Medicine, Ewha Womans University Mokdong Hospital, College of Medicine, Ewha Womans
University, Seoul, South Korea
j
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of
Medicine, Clinical Research Institute, Seoul National University Hospital, Lung Institute, Medical Research Center, Seoul
National University College of Medicine, Seoul, South Korea
k
Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea
University Anam Hospital, Seoul, South Korea
l
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan
University School of Medicine, Seoul, South Korea
m
Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine,
Seoul, South Korea

* Corresponding author. Tel.: 82 2 3010 3140; fax: 82 2 3010 6968.

E-mail address: sdlee@amc.seoul.kr (S.D. Lee).
o
Woo Jin Kim and Yeon-Mok Oh contributed equally to this article.

0954-6111/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2008.07.025

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CT phenotypes vary with the ADRB2 polymorphism 99

n
Respiratory Center, Seoul National University Bundang Hospital, Department of Internal Medicine, Seoul National
University College of Medicine, Seongnam, South Korea

Received 5 March 2008; accepted 25 July 2008

Available online 11 September 2008

KEYWORDS Summary
COPD; Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease that is
Polymorphism; characterized by varying degrees of involvement of airway and lung parenchyma. Although
Computed tomography cigarette smoke is the major risk factor for COPD, the principal determining factors of involve-
ment of the airway or lung parenchyma have not been clearly defined. Genetic variability in
COPD patients might influence the varying degrees of involvement of airway and parenchyma.
We therefore studied whether airway and parenchyma involvement might be associated with
the ADRB2 genotype, which has been reported to be associated with COPD susceptibility and
the bronchodilator response.
Methods: One hundred and eleven COPD subjects, whose post-bronchodilator FEV1/FVC values
were less than 0.7, and who had histories of smoking exceeding 10 pack-years, were prospec-
tively recruited from pulmonology clinics of 11 hospitals in Seoul, Korea. The degrees of
involvement of airway and parenchyma were evaluated by volumetric computed tomography
(CT) scans. In-house software automatically calculated luminal areas, airway wall areas,
percentages of wall areas in segmental bronchi, emphysema indices, and mean lung densities
in the whole lung parenchyma. The ADRB2 genotypes at codon 16 were determined for all
patients.
Results: Gly16 was associated with lumen diameter, luminal area, and percentage of wall area
in patients with COPD (p Z 0.02), whereas neither wall area nor wall thickness differed with
ADRB2 genotype. Neither emphysema index nor mean lung density was associated with ADRB2
genotype.
Conclusion: Gly16 variant in ADRB2 gene was associated with airway wall phenotypes
measured using CT scanning in COPD patients.
2008 Elsevier Ltd. All rights reserved.

Introduction there have been several reports regarding the association of

Chronic obstructive pulmonary disease (COPD) is defined as
airflow limitation measured by spirometry, and is a hetero-
geneous disease characterized by varying degrees of
involvement of airway and lung parenchyma.1 Chronic
inflammation and structural changes are the major patho-
logic features of COPD.1 Although some subjects show
emphysema as the predominant feature,2 remodeling in
airways is seen to various extents in COPD patients.3
Although cigarette smoking is the most important risk
factor, the mechanisms of persistent inflammation, the
causes of structural damage, and the factors that modify
the involvement of airway or parenchyma, have not been
clearly elucidated.
Computed tomography (CT) imaging is a useful tool in the
evaluation of morphological changes in COPD patients and
can also be helpful in evaluating heterogeneous COPD
phenotypes.4 CT phenotypes including airway wall thick-
ening, and emphysema severity, have been related to
different clinical characteristics and varying treatment
responsiveness in COPD,5 and such phenotypes may be useful
research biomarkers.6 Genetic variability in COPD patients
might explain persistent inflammation and the varying
degrees of involvement of airway and parenchyma. To date,
CT phenotypes and particular genotypes.7e9 The phenotypes
associated with particular genes are mainly the severity of
emphysema and emphysema distribution. Recent tech-
nology has made it possible to evaluate airway thick-
ness.10,11 Airway phenotypes can therefore be evaluated to
examine whether there might be an association between
such phenotypes and particular genotypes. A previous report
suggested that gender may influence airway lumen and
airway thickness.12 However, little research on the genetic
basis of airway thickness has been conducted.
ADRB2 is one of the most studied genes for COPD
susceptibility and work on this gene has yielded contra-
dictory results.13e15 Some data suggest that ADRB2 geno-
type may be associated with bronchodilator responsiveness
to both short-term and long-term use of b2-agonist in
asthma treatment.16,17
Recently, we developed volumetric CT analysis tools for
evaluation of emphysema and airway characteristics in
COPD patients.18 Quantified phenotypes of emphysema and
airway using volumetric CT might be helpful in searching for
more genetically homogeneous subgroups displaying
particular genetic influences.
We therefore investigated whether there might be an
association between emphysema and quantitative CT

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100
phenotypes of the airway, and ADRB2 genotypes on the
other, which could be associated with the pathogenesis of
airway disease in COPD patients.
Methods
Subjects and informed consent
The subjects for this study were extracted from a patient
cohort entitled The Korean Obstructive Lung Disease
(KOLD) Cohort, which consists of patients with chronic
obstructive pulmonary disease (COPD) or asthma. The KOLD
Cohort was designed primarily to develop a systematic
diagnostic model and an integrative prognostic factor of
obstructive lung diseases. For the KOLD Cohort, the
patients with chronic respiratory symptoms as well as
airflow limitation or bronchial hyperresponsiveness have
been and will be recruited in the pulmonary clinics of 11
hospitals in South Korea from June 2005 to October 2012.
For this study, a kind of interim analysis of the KOLD Cohort
study, a total of 145 patients were recruited from June 2005
to December 2006, and complete CT scanning data and
other clinical information, such as blood analysis and data
on pulmonary function were obtained.
In this study, the 118 COPD subjects extracted from the
KOLD Cohort of 145 patients met all of the following
criteria. They had post-bronchodilator FEV1/FVC values of
<0.7 and had more than 10 pack-years of smoking history as
well as no or minimal abnormalities on chest radiographs.
Among 118 COPD subjects, only 111 patients were analyzed
for this study after the exclusion of patients whose CT scans
were not performed adequately.
Our Institutional Review Board approved the analyses of
the clinical and imaging data. Individual informed written
consent was obtained from all patients.
Measurements of airway and lung parenchyma
using CT scans
Volumetric CT scans were performed on all patients using
16-channel, multidetector, CT machines of three manu-
facturers. These included the Somatom Sensation 16
(Siemens Medical Solutions, Forchheim, Germany), the GE
Lightspeed Ultra (General Electric Healthcare, Milwaukee,
WI), and the Philips Brilliance 16 (Philips Medical Systems,
Best, Netherlands). Patients were scanned during sus-
pended full inspiration and expiration in the supine posi-
tion. CT parameters used in the different CT scanners were
as follows: 16  0.75 mm collimation, 100 eff. mAs, 140 kVp
(Somatom Sensation 16); 16  0.625 mm, 300 mAs, 140 kVp,
Pitch 0.938, 0.5 s/rot (GE Lightspeed); and 16  0.75 mm,
133 mAs, 140 kVp, pitch 1, 0.75 s/rot (Philips 16). The
acquired data were reconstructed using a standard algo-
rithm with 0.625e0.8 mm thickness and 0.625e0.8 mm
increment. The CT machines were calibrated every week
with an AAPM standard phantom. The image data were
stored in the Digital Imaging and Communications in Medi-
cine (DICOM) format; this is the international standard for
interconnecting medical imaging devices on standard
networks.
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W.J. Kim et al.
Using in-house software, images of the whole lung were
extracted automatically, and the attenuation coefficient of
each pixel was measured and calculated. The cutoff level
between normal lung density and a low-attenuation area
was defined as 950 HU. From the CT data, the volume
fraction of the lung below 950 HU (V950) and the mean
lung density (MLD) were calculated automatically.
Measurements of the airway dimensions was performed
near the origins of segmental bronchi (RB1, LB1 2)
selected by a radiologist who was blind to clinical results,
using in-house software. The software automatically
detects the airway lumen, and the inner and outer bound-
aries of the airway wall, using a full-width-half-maximum
(FWHM) method. The FWHM method is typical of objective,
quantitative approaches to automatic airway measurement
methods.19e21 The software was validated using polyacryl
tubes with variable inner diameters and wall thick-
nesses.22,23 In each segmental bronchus, the airway
dimensions, including the wall area (WA), lumen area (LA),
and wall area percentage (WA %), were measured. The wall
area percentage was defined as WA % Z WA/
(WA LA)  100. The mean value of each segmental bron-
chus was used for statistical analysis. All of these analyses
were performed by one of the authors (YL) who was blind to
subjects background data.
Genotyping
ADRB2 genotyping was performed on all patients. Genomic
DNA was prepared from blood for genotype analysis.
Genotypes of codon 16 (rs1042713) were determined using
polymerase chain reaction and restriction fragment length
polymorphism (RFLP) techniques as previously described.16
Restriction digests were electrophoresed on 4% (w/v)
agarose gels and visualized using ethidium bromide.
Statistics
Analysis of variance (ANOVA) was used to analyze the
baseline characteristics to determine any differences
among genotypes. Statistical analyses of CT parameters
were used to determine any differences between geno-
types. HardyeWeinberg equilibrium was tested by the chi-
square method. Phenotypes tested included inspiratory
and expiratory emphysema indices, inspiratory and expi-
ratory mean lung densities, lumen area, lumen diameter,
wall thickness, wall area, and wall area percentage.
Inspiratory emphysema indices and expiratory emphysema
indices were log transformed to approximate normal
distributions. The associations between CT parameters and
ADBR2 genotype were examined under the additive model
assuming that an addition of each risk allele increases as
the same amount of risk. For example, the model assumes
that having two Gly alleles doubles the risk in comparison
to having one Gly allele. The analysis was adjusted for
age, gender, smoking status, body mass index (BMI), and
baseline FEV1. A random effect model was used where
hospital-influenced characteristics with CT phenotypes
were modeled as random errors24 using Proc Mixed
procedure of PC-SAS for Windows version 9.2 (SAS Insti-
tute, Cary, NC).
CT phenotypes vary with the ADRB2 polymorphism
Results
Characteristics of subjects
One hundred and eleven patients (108 men and 3 women)
were analyzed. Their mean (SD) age, FEV1, and smoking
history were 65.4  7.4 years (range 47e81 years),
1.48  0.57 L, and 45.9  25.0 pack-years, respectively.
Amongst the 111 COPD patients, 40 patients were of the
Arg/Arg genotype, 46 patients were Arg/Gly, and 25
patients were Gly/Gly. The prevalence of Arg16 poly-
morphisms did not significantly deviate from the Hardye
Weinberg equilibrium. The ages, FEV1 values, and smoking
histories were not significantly different amongst the three
groups of patients (Table 1).
Airway and lung parenchymal measurements using
CT scanning according to genotype
Lumen area was significantly smaller in patients with Gly16
(p Z 0.0225). Lumen diameter was significantly shorter
(p Z 0.0208) and wall area percentage was significantly
higher in the presence of the Gly allele (p Z 0.0205)
(Table 2). Airway wall thickness and wall area were not
associated with ADRB2 genotypes.
Inspiratory emphysema index, inspiratory mean lung
density, expiratory emphysema index, and expiratory mean
lung density did not vary with ADRB2 codon 16 genotype
(Table 3).
Discussion
In this study, lumen area, lumen diameter and wall area
percentage of airway were associated with the ADRB2
genotype whereas emphysema phenotypes were not. Our
finding is the first report suggesting that genetic variability
may influence airway phenotypes in COPD patients.
Our finding that COPD patients with the Gly16 allele in
the ADRB2 showed smaller lumen areas and larger wall area
percentages could be explained in several ways.
Firstly, the Gly16 allele in the ADRB2 might increase
susceptibility to COPD. A report in Chinese claimed that
Gly16 increased susceptibility to COPD.15 Although the
claim was not supported by other reports of inconsistent
Table 1 Baseline characteristics of 111 subjects with
COPD by ADRB2 genotypes.
Genotype Arg/Arg Arg/Gly Gly/Gly
Number of 40 (39/1) 46 (45/1) 25(24/1)
subjects
(male/female)
Age (years) 65.3  6.6 65.0  8.5 66.3  6.5 0.76
Baseline 1.41  0.58 1.53  0.53 1.45  0.56 0.56
FEV1 (L)
Smoking 46.4  25.5 50.0  27.2 38.3  17.8 0.17
(pack-years)
Data are presented as mean (SD), unless otherwise noted.
Analysis of variance (ANOVA) was used to calculate p values.
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101
Table 2 Airway wall indices using CT scanning according
to ADRB2 genotype.
Genotype Arg/Arg Arg/Gly Gly/Gly p value
Lumen 11.1  2.9 10.7  2.6 9.5  3.0 0.02
area
(mm2)
Lumen 3.63  0.48 3.58  0.46 3.34  0.55 0.02
diameter
(mm)
Airway 1.23  0.12 1.21  0.12 1.24  0.10 0.59
thickness
(mm)
Wall area 17.8  5.4 17.7  5.2 16.4  6.0 0.22
(mm2)
Wall area (%) 63.6  4.2 63.7  4.2 66.4  5.4 0.02
Mean values (SEM) for data are shown. Associations of gly16
polymorphism and CT parameters were estimated assuming
additive genetic model (adjusting age, sex, smoking, FEV1, BMI,
and random effects of recruited hospitals).
findings,13,25 as race could have influenced association
results, our finding suggesting smaller lumen areas in Gly16
alleles is compatible with the work showing the risk of
COPD in Chinese subjects with Gly16 alleles.
Second, the Gly16 allele in ADRB2 might be related to
a greater degree of airway obstruction. A previous report
demonstrated that Gly16 was associated with better
response to the long-term use of a short acting b2-
agonist,17,26 leading others to hypothesize that a greater
obstruction at baseline leads to better response to bron-
chodilator treatment in patients with the Gly16 genotype.27
Our findings also support the hypothesis that more
obstruction is seen in patients with the Gly16 allele.
Lastly, Gly16 allele in the ADRB2 might be associated
with the chronic bronchitis subtype. Previous report
revealed that COPD patients with chronic bronchitis
symptoms showed higher wall area percentage and thick-
ness to diameter than COPD patients without chronic
bronchitis symptoms.28 In our study, ADRB2 genotype was
associated with wall area percentage but not with wall
thickness nor with wall area. This result suggests an asso-
ciation with chronic bronchitis. However, we cannot rule
out the possibility that this genotype is related to lumen
dilation but not to airway wall phenotype. This warrants
further research.
Our finding that genetic variability in the ADRB2 may
influence airway phenotypes in COPD patients could raise
p Value an important issue in clinical practice. Since airway
phenotypes are important in COPD, factors influencing
these phenotypes can be a target for drug development.
There are some limitations in this study. First, according
to a recent report results may differ with the use of various
types of CT scanners, and with the radiation doses used.29
To minimize the variation of the result, we modified the
imaging protocols with similar reconstruction methods,
resolution, and radiation dose. However, usage of different
machines from different vendors with different imaging
protocols may increase the measurement errors, resulting
in weakening the correlation with the CT phenotypes.
102
Table 3 Emphysema indices according to ADRB2 genotype.
Genotype Arg/Arg
Inspiratory emphysema 24.4  16.2
index (%)
Inspiratory mean 887.4  24.3
lung density (HU)
Expiratory emphysema 14.0  14.1
index (%)
Expiratory mean 839  45.2
lung density (HU)
Mean values (SEM) for data are shown. Associations of gly16 polymorphism and CT parameters were estimated assuming additive
genetic model (adjusting age, sex, smoking, FEV1, BMI, and random effects of recruited hospitals).
Secondly, we could not measure small airways, but
rather only large airways, so this study may only reflect
large airways. According to one study, however, large
airway data parallel information from small airways.30
Thirdly, we analyzed only codon 16 in our ADRB2 geno-
typing. It is suggested that ADRB216 is of functional impor-
tance and this genotype has been extensively studied in both
clinical trials, and to define functional aspects of COPD.17,27
Although there may be unsuspected between-race differ-
ences in the importance of this codon, and although explo-
ration of other haplotypes might be informative,31 codon 16
seems, at present, to be the most informative.
Lastly, most of our patients were male, and there may
be gender differences in CT phenotypes of COPD subjects.12
Our results may therefore not apply to female patients.
In conclusion, ADRB2 gene polymorphism was associated
with airway wall phenotypes measured using CT scanning in
COPD patients. CT phenotype differences may be related to
different subtypes that may be explained by genetic
factors. Future research might include replication in addi-
tional cohorts and identification of functional relevance.
Conflict of interest
None declared.
Acknowledgment
This study was supported by a grant from the Korean Health
21 R&D Project, Ministry of Health and Welfare, Republic of
Korea (A040153).
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