The association of plasma biomarkers with computed tomography

Carolan et al. Respiratory Research 2014, 15:127
Open Access
The association of plasma biomarkers with
computed tomography-assessed emphysema
Brendan J Carolan1,2*, Grant Hughes3, Jarrett Morrow4, Craig P Hersh4, Wanda K O’Neal5, Stephen Rennard6,
Sreekumar G Pillai7,12, Paula Belloni8,12, Debra A Cockayne9, Alejandro P Comellas10, Meilan Han11,
Rachel L Zemans1,2, Katerina Kechris3 and Russell P Bowler1,2
Rationale: Chronic obstructive pulmonary disease (COPD) is a phenotypically heterogeneous disease. In COPD, the
presence of emphysema is associated with increased mortality and risk of lung cancer. High resolution computed
tomography (HRCT) scans are useful in quantifying emphysema but are associated with radiation exposure and
high incidence of false positive findings (i.e., nodules). Using a comprehensive biomarker panel, we sought to
determine if there was a peripheral blood biomarker signature of emphysema.
Methods: 114 plasma biomarkers were measured using a custom assay in 588 individuals enrolled in the
COPDGene study. Quantitative emphysema measurements included percent low lung attenuation (%LAA) ≤ −950
HU, ≤ − 910 HU and mean lung attenuation at the 15th percentile on lung attenuation curve (LP15A). Multiple
regression analysis was performed to determine plasma biomarkers associated with emphysema independent of
covariates age, gender, smoking status, body mass index and FEV1. The findings were subsequently validated using
baseline blood samples from a separate cohort of 388 subjects enrolled in the Treatment of Emphysema with a
Selective Retinoid Agonist (TESRA) study.
Results: Regression analysis identified multiple biomarkers associated with CT-assessed emphysema in COPDGene,
including advanced glycosylation end-products receptor (AGER or RAGE, p < 0.001), intercellular adhesion molecule 1
(ICAM, p < 0.001), and chemokine ligand 20 (CCL20, p < 0.001). Validation in the TESRA cohort revealed significant
associations with RAGE, ICAM1, and CCL20 with radiologic emphysema (p < 0.001 after meta-analysis). Other biomarkers
that were associated with emphysema include CDH1, CDH 13 and SERPINA7, but were not available for validation in
the TESRA study. Receiver operating characteristics analysis demonstrated a benefit of adding a biomarker panel to
clinical covariates for detecting emphysema, especially in those without severe airflow limitation (AUC 0.85).
Conclusions: Our findings, suggest that a panel of blood biomarkers including sRAGE, ICAM1 and CCL20 may serve as
a useful surrogate measure of emphysema, and when combined with clinical covariates, may be useful clinically in
predicting the presence of emphysema compared to just using covariates alone, especially in those with less severe
COPD. Ultimately biomarkers may shed light on disease pathogenesis, providing targets for new treatments.
Keywords: COPD, Biomarkers, RAGE, ICAM1, CCL20, Emphysema
* Correspondence: [email protected]
Department of Medicine, National Jewish Health, 1400 Jackson St, Denver,
CO 80206, USA
Department of Medicine, University of Colorado School of Medicine, Aurora,
Full list of author information is available at the end of the article
© 2014 Carolan et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver ( applies to the data made available in this article,
unless otherwise stated.
Carolan et al. Respiratory Research 2014, 15:127
Chronic obstructive pulmonary disease (COPD) is a
phenotypically heterogeneous condition characterized by
airflow limitation that is not fully reversible [1]. Some, but
not all, COPD subjects have emphysema, i.e., airspace enlargement distal to the terminal bronchioles [2]. Determining the presence of emphysema is important, as it has
been independently associated with increased respiratory
symptoms, more rapid decline in lung function, increased
risk of lung cancer, higher rates of cardiovascular disease
and increased mortality risk [3-6]. Surprisingly, there are
some subjects with significant smoking history that have
emphysema, but no airflow limitation [7]. Understanding
the molecular signatures underlying emphysema may shed
light on the pathogenesis of emphysema and its systemic
The best current non-invasive method of detecting emphysema is high-resolution computed tomography
(HRCT) [8,9]. The drawbacks to HRCT include cost, radiation exposure, and a high rate of false positive clinical significant findings (e.g. benign nodules); however, HRCT can
provide significant information relevant to lung pathology.
For instance, lung attenuation area (LAA) at −950 or −910
Hounsfield units (HU) and the mean lung attenuation
value at the 15th percentile (LP15A) on the lung attenuation curve are density-based measurements that correlate
with emphysema [8,10,11]. Although the optimal method
and normal values for describing radiologic emphysema
have not been fully validated, it has been shown that control smokers without COPD have percent LAA ≤ −950
HU of <5% [9].
The first reported blood biomarker of emphysema was
α1-antitrypsin (AAT); however, AAT deficiency accounts
for only 1-2% of COPD [12]. Another recently reported independent biomarker of emphysema is soluble RAGE or
advanced glycosylation end product receptor (AGER) [13].
Peripheral blood adiponectin and bronchoalveolar lavage
fluid eotaxin levels have also correlated with radiologic
emphysema [14,15]. There are other reports of peripheral
blood biomarkers of airflow limitation such as interleukin6, surfactant protein D and C-reactive protein [16,17].
Therefore, the presence of systemic biomarkers in peripheral blood, which can be easily measured and offer information regarding COPD phenotypes, may provide another
method of significant value in diagnosing and managing
individuals with emphysema [18]. In addition, a biomarker
signature of emphysematous phenotypes may provide
insight to the pathogenesis of disease. Limitations of some
previous emphysema biomarker studies include small
sample size and lack of replication. With this in mind,
using one of the largest studies to date, we sought to determine a peripheral blood biomarker signature of emphysema, independent of other clinical variables, in current
and former cigarette smokers with normal lung function
Page 2 of 10
and with COPD, and relate the biomarker signature to different methods of defining radiologic emphysema. Key
findings were validated in an independent COPD cohort.
Study population
COPDGene is a multi-centered study of the genetic epidemiology of COPD that enrolled 10,192 non-Hispanic
White and African-American individuals, aged 45–80
years old with at least a 10 pack-year history of smoking,
who had not had an exacerbation of COPD for at least
the previous 30 days. Additional information on the
COPDGene study and the collection of clinical data has
been described previously [19]. 1839 COPDGene subjects (1599 non-Hispanic White (NHW) and 240 nonHispanic Black) had fresh frozen plasma collected using a
p100 tube (BD) at five COPDGene sites (National Jewish
Health (N =916), University of Iowa (N =670), HarborUCLA Medical Center (N =202), Temple University
(N =36), and Baylor Medical Center (N =15)). From this
cohort a subset of 602 NHW subjects (no non-Hispanic
Black subjects included due to limited numbers) were selected for a comprehensive biomarker study with an attempt to obtain a range of GOLD stages and match groups
as closely as possible based on age, gender and smoking
history. Of the 602 subjects, 588 subjects had quantitative
HRCT measurements available. The institutional review
boards of participating institutions approved the study
(Additional file 1: Table S1).
A separate validation cohort of 388 individuals (all former
smokers with COPD) was obtained from the Treatment of
Emphysema with a Selective Retinoid Agonist (TESRA)
study. TESRA was a multi-centered randomized controlled
trial assessing the safety and efficacy of palovarotene in exsmokers with COPD. Only baseline samples before treatment were used for biomarker determination. Emphysema
was quantitatively assessed by low dose spiral CT in the
TESRA cohort. Additional information on the TESRA
study has been described previously [20].
Clinical data and definitions
COPD was defined as post bronchodilator ratio of forced
expiratory volume in the first second (FEV1) to forced vital
capacity (FVC) <0.70. Current or ex-smokers without spirometric evidence of airflow obstruction (FEV1/FVC ≥0.70)
were classified as controls [1].
COPDGene study patients underwent whole lung volumetric multi-detector computed tomography (CT) as previously described [19,21]. Quantitative analysis of lung
density was performed using the Slicer software package
( Emphysema was primarily quantified by the percent of lung voxels (%LAA) ≤ −950 HU on
the inspiratory images of CT scans for the whole lung.
Emphysema was additionally quantified by percent of lung
Carolan et al. Respiratory Research 2014, 15:127
voxels (%LAA) ≤ −910 HU on inspiratory CT scans
and as mean lung attenuation at the 15th percentile
on lung volume-adjusted attenuation curve (LP15A).
In the TESRA cohort emphysema was quantified as
%LAA ≤ −910 HU and LP15A on HRCT scans [20].
Densiometric analyses of the HRCTs were completed in
a central lab (BioClinica, Leiden, The Netherlands)
using PulmoCMS software (Medis specials, Leiden, The
Netherlands). The study design and clinical outcomes
have been previously reported [13,20].
Biomarker selection and measurement
For the COPDGene cohort, 114 candidate biomarkers
were selected based on a review of the literature and previously reported pilot work from the BIOSPIR group [22].
Biomarker levels were determined using a custom 15-panel
assay created by Myriad-RBM (Austin, TX) multiplex technology. Blood samples were drawn from non-fasting individuals. Approximately 8.5 mL of blood was withdrawn
from the ante-cubital vein into a sterile 13 × 1000 mm
P100 Blood Collection Tube (BD, New Jersey, USA). The
sample was immediately centrifuged at 2500 × g, 20 minutes
at room temperature. Aliquots in 500 μL tubes were
stored at −80°C until analyzed. In the TESRA cohort, 111
similarly chosen protein biomarkers were measured in
ethylenediamine-tetraacetic acid (EDTA) plasma in duplicate at Rules Based Medicine (Austin, TX) and Quest
Diagnostics (Valencia, CA). A full list of biomarkers analyzed in the TESRA study has been published [13]
Statistical analysis
Differences in demographic characteristics of study
subjects were analyzed using a t-test for continuous
variables and a Chi-squared test for categorical variables. Emphysema severity was classified as none, mild,
moderate and severe. For %LAA ≤ −950 HU the cutoffs
were <5%, 5- < 10%, 10- < 20% and ≥20%, respectively,
while for %LAA ≤ −910 HU the cutoffs were <35%, 35- <
45%, 45- < 55% and ≥55%, respectively. Cutoffs were based
on mean values from COPDGene studies and balancing
the sample size in each group [9].
Biomarkers (n = 17) with >10% and <95% of values
below the lower limit of quantitation (LLOQ) for that particular biomarker were transformed into binary variables
(present or absent). Biomarkers (n = 16) with >95% values
below LLOQ were excluded from the analysis. For regression analysis, the remaining biomarker levels (n = 81)
underwent an empirical normal quantile transformation
projecting the ranks onto an inverse normal distribution
so that they resemble a normal distribution and allow comparison of biomarkers at different concentrations. Nontransformed biomarker levels are also presented (Additional
file 1: Table S3). Collinearity among biomarkers and covariates was assessed using Pearson correlation. Collinearity
Page 3 of 10
(R > 0.6) was observed between proinsulin intact (INS intact) and proinsulin total (INS total) so INS intact was
removed from the analysis. Also, brain derived neurotropic factor (BDNF) was removed, as it was collinear with
angiopoietin 1, CCL5 (T cell specific protein RANTES),
epithelial-derived neutrophil-activating protein 78, alpha-1
antitrypsin and latency associated peptide of transforming
growth factor beta 1. For modeling of multiple biomarkers,
stepwise regression, with a combination of backwards
and forwards selection and a p-value threshold <0.15
for entry and exit from the model, was used to arrive at
the final model. A p-value of <0.05 was taken as statistically significant for association with the outcome emphysema variables.
To perform the meta-analysis, a single variable model
was fit for each of the significant biomarkers that were also
identified in the TESRA study. Equivalent covariates were
included for the two studies and an ordered logistic and linear regression was fit respectively for the %LAA ≤ −910 HU
and LP15A outcomes. P-values from both studies were
combined by calculating the average Z-score of the inverse
normal quantiles of the two p-values to determine a combined p-value that accounted for consistent effects of the
biomarker levels on emphysema severity in the two studies
[23]. A Bonferroni adjustment was applied based on all
tested markers.
Receiver operating characteristic (ROC) curves were
generated for covariates alone and covariates with biomarkers with the presence of emphysema compared to
no emphysema as the outcome. Nominal logistic regression was performed, with emphysema considered
present if %LAA ≤ −950 HU was ≥5% compared to no emphysema (%LAA ≤ −950 HU <5%). Similarly, ROC curves
were generated including different severities of airflow limitation based on FEV1 percent predicted. Statistical analyses
were performed using JMP 9.0 (SAS Institute, Cary, NC)
and R (version 3.0.2) statistical software packages [24].
Study population
Demographics, physiology, quantitative HRCT measurements and patient-reported outcomes for COPDGene
and TESRA cohorts are listed in Table 1. In the COPDGene biomarker study, there were 588 individuals with
complete data available. Subjects with COPD were significantly older, had lower BMI, higher pack-year history
of smoking and worse SGRQ scores compared to those
without COPD (p < 0.01, all comparisons). The distribution of gender and current smokers was similar between
non-COPD and COPD groups. The following variables
were associated with emphysema (LAA ≤ −950 HU): lower
FEV1 (p < 0.001), lower body mass index (p < 0.001), male
gender (p = 0.002), older age at enrollment (p = 0.038) and
current non-smoking status (p < 0.001); these variables
Carolan et al. Respiratory Research 2014, 15:127
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Table 1 Demographics of individuals in COPDGene and TESRA studies*
COPDGene (n = 588)
n = 247
n = 341
(n = 388)
Age (years)
61 ± 3
65 ± 0.5
p < 0.01
66.6 ± 0.4
Gender (male/female)
p = 0.63
Current smokers (%)
p = 0.23
Smoking history (pack-years)
38 ± 1
54 ± 2
p < 0.001
48 ± 1
Body mass index (kg/m2)
28.9 ± 2.3
27.8 ± 0.3
p = 0.009
26 ± 0.2
FEV1 post bronchodilator (% predicted)
98 ± 3.6
47 ± 1
p < 0.001
50 ± 0.5
FVC post bronchodilator (% predicted)
96 ± 3.6
79 ± 1
p < 0.001
93 ± 0.9
2.3 ± 1.6
15 ± 0.7
p < 0.001
% Emphysema <5%
% Emphysema 5- <10%
% Emphysema 10- <20%
% Emphysema ≥ 20%
HRCT measurements
Average % LAA ≤ −950 HU
Average % LAA ≤ −910 HU
22.6 ± 3.7
39 ± 0.7
% Emphysema <35%
% Emphysema 35- <45%
% Emphysema 45- <55%
% Emphysema ≥55%
−916 ± 4.3
MRC dyspnea score
Average LP15A
p < 0.001
40.7 ± 0.8
−944 ± 1.3
p < 0.001
−945 ± 1.3
0.5 ± 0.1
2.2 ± 0.1
p < 0.001
2.0 ± 0.03
12 ± 3.9
39 ± 1.1
p < 0.001
46 ± 0.8
Patient-reported outcomes
*Presented are the means ± standard errors for COPDGene cohort and TESRA cohort. p values represent difference between no COPD and COPD groups for
COPDGene. FEV1 = Forced expiratory volume at one second; FVC = forced vital capacity; LAA = low area attenuation; N/A = data not available; LP15A = mean lung
attenuation value at the 15th percentile on lung attenuation curve. MRC = Medical Research Council; SGRQ = St. George’s Respiratory Questionnaire.
were used as covariates for multiple regression (Additional
file 1: Table S2).
Biomarkers associated with emphysema
A full list of biomarkers analyzed in the COPDGene cohort
is available (Additional file 1: Table S3). After adjusting for
covariates, multiple regression analyses demonstrated a
total of 24 biomarkers associated with radiologic emphysema including 15 biomarkers independently associated
with %LAA ≤ −950 HU (R2 = 0.4), 9 biomarkers associated
with %LAA ≤ −910 HU (R2 = 0.36) and 16 associated with
LP15A (R2 = 0.64, Table 2). There were 6 biomarkers that
were associated with all 3 radiologic emphysema outcome
variables. Advanced glycosylation end-product receptor
(RAGE) was negatively associated with more severe emphysema (Figure 1A). In addition, intercellular adhesion molecule 1 (ICAM1, Figure 1B), macrophage inhibitory protein
3a (CCL20) and cadherin 1 (CDH1, Figure 1C) were negatively associated with emphysema severity. Cadherin 13
(CDH13, Figure 1D) and thyroxin-binding globulin (SERPINA7) were positively correlated with emphysema severity (p < 0.001 for all comparisons). There were 3
biomarkers surfactant associated protein D (SFPD), FAS
ligand receptor (FAS), and malondialdehyde-modified
low-density lipoprotein (MDA LDL) associated with
both %LAA ≤ −910 HU and LP 15 emphysema outcomes (Table 2).
Validation of emphysema biomarkers
Using similar statistical methods (modeling, covariates,
etc.), we attempted to validate the statistically significant
biomarkers using an independent cohort from the
TESRA study. Although %LAA ≤ −910 HU and LP15A
HRCT data were available in the TESRA cohort, %
LAA ≤ −950 HU measurements were not. Therefore, of
the total 16 biomarkers statistically associated with the
emphysema outcomes ≤ −910 and LP15A in the COPDGene cohort, 9 biomarkers were available for validation
Carolan et al. Respiratory Research 2014, 15:127
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Table 2 Biomarkers and covariates associated with radiologic emphysema in the COPDGene cohort
(using multiple regression)*
%LAA ≤ −950 HU
%LAA ≤ −910 HU
Beta coefficient
Beta coefficient
Beta coefficient
FEV1 (% predicted)
2.9 × 10−40
6.4 × 10−29
2.1 × 10−47
Body mass index
3.2 × 10−10
8.2 × 10−22
3.4 × 10−21
Current active smoking
9.1 × 10
1.3 × 10
7.5 × 10−7
Male gender
7.3 × 10−9
Age at enrollment
2.6 × 10−8
CCL20 (presence)
3.4 × 10−6
IL12B (presence)
MDA LDL (absence)¶
*Presented are beta coefficients and p values for multiple regression models of biomarkers and covariates associated with emphysema outcomes. %LAA = Percent
low attenuation areas; LP15A = mean lung attenuation at 15th percentile on lung attenuation curve; HU = Hounsfield units; FEV1 = Forced expiratory volume in 1st
second; RAGE = Receptor for advanced glycosylation end products; CCL20 = Macrophage Inflammatory Protein-3 alpha; ICAM1 = Intercellular Adhesion Molecule 1;
SERPINA7 = Thyroxin-binding globulin; CDH 13 = Cadherin-13; CDH1 = Cadherin-1; TGFB1 LAP = Latency-Associated Peptide of Transforming Growth Factor beta 1;
CCL13 = Monocyte Chemotactic Protein 4; TNFRSF11B = Osteoprotegerin; CCL8 = Monocyte Chemotactic Protein 2; IgA = Immunoglobulin A; SORT1 = Sortilin; IL2RA =
Interleukin-2 receptor alpha; CCL2 = Monocyte Chemotactic Protein 1; IL-12B = Interleukin-12 Subunit p40; MDA LDL = Malondialdehyde-Modified Low-Density Lipoprotein;
FAS = FASLG Receptor; SFTPD = Surfactant protein D; AXL = AXL Receptor Tyrosine Kinase; CXCL10 = Interferon gamma Induced Protein 10; ADIPOQ = Adiponectin; MB =
Myoglobin; SOD1 = Superoxide dismutase 1; NRCAM = Neuronal Cell Adhesion Molecule.
Higher LP15A values indicate less severe emphysema, so positive coefficients are associated with less severe emphysema and negative coefficients are associated
with more severe emphysema unlike higher %LAA which is associated with more severe emphysema.
Biomarkers not available for replication in TESRA.
in TESRA cohort. After meta-analysis and adjustment
for multiple testing, biomarkers RAGE (p = 1.2 × 10−9)
and ICAM1 (p = 1.5 × 10−7) were associated with %
LAA < −910 HU (Table 3). Similarly, with regard to the
LP15A emphysema outcome variable, meta-analysis
with the TESRA cohort validated the association of
RAGE (p = 2.5 × 10−10), ICAM1 (p = 6.0 × 10−11), and
AXL (p = 3.8 × 10−3) with radiologic emphysema independent of covariates (Table 3). CCL20 was significantly negatively associated with emphysema in both
the TESRA and COPDGene cohorts; however, metaanalysis was not possible due to CCL20 being binary in
Carolan et al. Respiratory Research 2014, 15:127
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Figure 1 Biomarkers associated with CT-assessed emphysema in the COPDGene cohort. (A) Advanced glycosylation end-product receptor
(RAGE); (B) Intracellular adhesion molecule 1 (ICAM1); (C) Cadherin 1 (CDH1); (D) Cadherin 13 (CDH13). *Presented are normal quantile transformed
biomarker levels on the ordinate and percent emphysema (% low attenuation ≤ −950 HU) on CT scan on abscissa (p < 0.001 for all comparisons).
Table 3 Meta-analysis of biomarkers associated with emphysema in COPDGene and TESRA cohorts*
Beta coefficient
Beta coefficient
2.6 × 10−5
9.2 × 10−7
9.2 × 10
3.4 × 10
1.5 × 10−7
1.3 × 10−4
2.2 × 10−3
1.3 × 10−5
3.0 × 10−8
2.5 × 10 −10
Percent LAA ≤ −910 HU
1.2 × 10 −9
Mean lung attenuation at 15 percentile
1.1 × 10
4.5 × 10
6.0 × 10−11
1.8 × 10−4
3.8 × 10−3
8.2 × 10
1.3 × 10
*Presented is the regression analysis for each biomarker with an adjusted meta-analysis p value. LAA = low attenuation area; RAGE = Receptor for advanced
glycosylation end products; ICAM1 = Intercellular Adhesion Molecule 1; CCL20 = Macrophage Inflammatory Protein-3 alpha; AXL = AXL Receptor Tyrosine Kinase;
°p values for COPDGene and TESRA are two-sided p values.
CCL20 was a binary variable in COPDGene, therefore it is the presence CCL20 that is negatively associated with emphysema in COPDGene cohort, while CCL20 was a
continuous variable in TESRA also associated negatively associated with more severe emphysema. Meta-analysis was not possible given difference in variables (N/A).
Carolan et al. Respiratory Research 2014, 15:127
COPDGene and continuous in TESRA. Biomarkers
significant in the COPDGene study such as CDH1,
ADIPOQ were not measured in the TESRA study and
therefore could not be included in the meta-analysis.
ROC curves for covariates age, gender, BMI, current
smoking status and FEV1 had an area under the curve
(AUC) of 0.88 for the prediction of emphysema. ROC
curves demonstrated a slight improvement in the AUC
after adding 15 biomarkers to the model, raising the
AUC to 0.92 (Additional file 1: Table S4 and Figure S1).
However, when only considering those without severe
airflow limitation (FEV1 ≥ 50%, n = 399), the AUC was
0.78 using covariates alone and the AUC increased to
0.85 when the biomarker panel was added to the model.
COPD is a phenotypically heterogeneous disease, with the
presence of emphysema having implications for risk stratification and management [3-5,18]. In this study, we successfully identified and replicated a panel of peripheral blood
biomarkers that was associated with emphysema independent of age, smoking status, body mass index, airflow limitation, and gender. These biomarkers (AGER, ICAM1 and
CCL20) were associated with emphysema regardless of
quantification technique (%LAA ≤ −950 and ≤ −910 HU
and LP15A) and were replicated in an independent
COPD cohort (TESRA), thus strengthening their potential utility for defining clinically relevant emphysema.
Our study reports lower RAGE levels in peripheral
blood as a biomarker of increased emphysema percentage in the lungs independent of gender, age, airflow limitation, body mass index and current smoking status.
RAGE (advanced glycosylation end-product receptor or
AGER) is an immunoglobulin family member that is
highly expressed in human lung [25]. The RAGE pathway and soluble RAGE (sRAGE), a splice variant or proteolytic cleavage product of RAGE, have been associated
with several inflammatory conditions such as diabetes
mellitus, vascular disease and arthritis [26,27]. The sRAGE
molecule binds damaged ligands preventing these from
binding to cell surface receptors and activating cell signaling pathways [28]. RAGE is active in damage-related conditions such as hyperglycemia, hypoxia, inflammation and
oxidative stress [29]. While fasting blood glucose measurements were not available, 66 individuals reported a history
of diabetes mellitus in the COPDGene biomarker study
and there was no association between RAGE levels and
self-reported history of diabetes mellitus (p = 0.88). Lower
levels of sRAGE have been described in individuals with
airflow limitation [30,31]. Other studies have found lower
sRAGE levels associated with CT-assessed emphysema severity and cor pulmonale [32] and with CT-assessed emphysema and lower diffusing capacity of carbon monoxide
Page 7 of 10
using the TESRA data described in this study in combination with the ECLIPSE investigators [13]. Some studies
suggest that sRAGE is increased in the lungs of patients
with COPD and high levels of sRAGE may be associated
with progression of emphysema [33]. Interestingly, animal
studies suggest RAGE/sRAGE plays a role in alveolar development and overexpression in mouse lung leads to
the development of emphysema [34]. This suggests that
sRAGE, by acting as a decoy molecule, may have a different role in the developing lung and the adult lung or low
sRAGE levels in COPD may result in increased inflammatory signaling in the lung.
In the present study, we found decreased ICAM1
levels correlate with increased severity of emphysema on
CT scan, independent of smoking status, FEV1 and other
covariates. ICAM1 is expressed on vascular endothelial
and immune cells and mediates cell transmigration and
adhesion [35]. ICAM1 plays a role in the recruitment of
inflammatory cells to the lung. There is currently quite
limited information about the association of ICAM1 to
COPD and emphysema. Higher serum levels of soluble
ICAM1 have been demonstrated in COPD, where it correlated with the severity of airflow limitation, arterial
hypoxemia and hypercarbia [36,37]. Other studies relate
ICAM1 levels to active smoking [38] and preliminary
analysis from The MESA Lung Study demonstrated that
ICAM1 predicted 0.15%/year increase in CT-assessed
emphysema, suggesting a role for this molecule as a biomarker of emphysema and that it may play a role in emphysema pathogenesis [39].
CCL20 or macrophage inhibitory protein 3a, a chemokine receptor ligand, is involved in the recruitment of inflammatory cells through chemokine receptor 6 (CCR6),
its only known receptor [40]. In both the COPDGene
study and the TESRA study, CCL20 levels were inversely
and significantly associated with emphysema although
methodological considerations prevented a meta-analysis.
Lower CCL20 levels have been described in bronchoalveolar lavage fluid of smokers [41]. The CCR6/CCL20 complex is one of the most potent regulators of dendritic cell
migration to the lung and CCR6 knockout mice may be
partially protected against cigarette smoke-induced emphysema due to reduced recruitment of inflammatory cells
to the lung [42]. These data suggest that increased activity
of the CCL20/CCR6 pathway may increase the susceptibility to emphysema.
CDH1 was negatively correlated with radiologic emphysema across all emphysema outcome measurements.
CDH1 or E cadherin is an epithelial cell adhesion molecule
that regulates cell differentiation and morphogenesis, and is
associated with lung fibrosis and cancer [43]. CDH1 may
be a marker of epithelial cell injury and epithelial to mesenchymal transition that is believed to play a role in small airway remodeling in COPD [44]. Genetic polymorphisms in
Carolan et al. Respiratory Research 2014, 15:127
CDH1 have been associated with development of COPD
and decline in lung function [45]. CDH13 or H cadherin is
another adhesion molecule that may influence surfactant
protein D levels and serum adiponectin levels, both implicated in the pathogenesis of COPD; however, CDH13 itself
has not been associated with quantitative emphysema to
date [46,47]. We found higher levels of CDH13 to be associated with CT-assessed emphysema in the COPDGene
cohort, but these were not available for validation in the
TESRA cohort. Higher SERPINA7 levels were also associated with more radiologic emphysema. SERPINA7 does
not have protease inhibitor capabilities and is also known
as thyroid binding globulin. This study represents a new
association for SERPINA7 with COPD.
With regard to the ability of biomarkers to predict the
presence of any emphysema compared to no emphysema,
ROC curves demonstrated a small contribution of plasma
biomarkers separate to the covariates alone. This is likely
because when individuals with more severe levels of emphysema are included, covariates alone, especially FEV1, are
highly predictive of emphysema in their own right. However, the biomarkers are more useful for predicting the
presence of emphysema in those that do not already have
severe airflow limitation, because the covariates alone were
not as good at predicting emphysema in this group and
biomarkers combined with covariates increased the area
under the curve. This may be useful clinically since determining the presence of underlying emphysema at this early
stage in those that do not yet have severe airflow limitation
may have outcome benefits for the individuals [3-6].
This COPDGene biomarker study is one of the largest
emphysema biomarker studies to date on carefully phenotyped individuals with COPD. The TESRA cohort provides validation of a number of the findings. The study
confirms a previously identified association between radiologic emphysema and sRAGE, builds on data suggesting a
role for ICAM1 as a biomarker, in addition to discovering
previously not identified biomarkers associated with emphysema such as CCL20, cadherin 1, cadherin 13 and
SERPINA7. The study also highlights the potential usefulness of a panel of biomarkers to predict the presence of
emphysema compared to using clinical data alone, especially in those who do not yet have severe abnormalities in
lung function. However there are limitations; the TESRA
cohort was different from the COPDGene cohort in that
its population was comprised of ex-smokers with at least
mild COPD and did not include control subjects and only
2 of the 3 quantitative emphysema measurements were
made (−910 HU and LP15A). Since emphysema can occur
in smokers without COPD and emphysema measurements
are highly co-linear, these limitations may be of minor importance. Other limitations include the fact that the majority of subjects in both cohorts were non-Hispanic
white, thus, the generalizability of these findings to other
Page 8 of 10
populations remains unknown and emphysema measurements from both COPDGene and TESRA were cross sectional; therefore, the significance of these biomarkers for
emphysema progression remains unknown. A final limitation of this study, an in many biomarker studies, is the
magnitude of association between the change in biomarker
levels and the change in emphysema severity. While the
biomarker associations are highly statistically significant,
and validation suggests the associations are real, further
studies are needed to evaluate the role of these biomarkers
in disease pathogenesis and as markers of disease presence
and progression [48,49].
Our findings, particularly when combined with other
studies of individual biomarkers, suggest that a panel of
blood biomarkers including sRAGE, ICAM1 and CCL20
may serve as a useful surrogate measure of emphysema
and may shed light on disease pathogenesis, providing
targets for new treatments. Other biomarkers such as
CHD1, CDH13 and SERPINA7 may also have a role in
evaluating emphysema (especially milder emphysema), although require confirmation in other cohorts. Overall,
these peripheral blood biomarkers could ultimately be
used to diagnose emphysema at subclinical stages thereby
reducing the need for CT, and perhaps may provide insights into disease prediction and progression.
Additional file
Additional file 1: Table S1. Institutional Review Boards of Participating
Institutions. Table S2. Demographics of COPDGene cohort. Table S3.
Biomarkers in COPDGene biomarker study*. Table S4. Area under curve
(AUC) for receiver operating characteristic (ROC) curves derived for
emphysema (%LAA< -950 HU ≥5%) vs. no emphysema (%LAA< -950
HU <5%) as outcome*. Figure S1. *Receiver operating characteristic
(ROC) curve with emphysema (%LAA< -950 HU ≥5%) vs. no emphysema
(%LAA< -950 HU <5%) as outcome for (A) covariates age, gender, body
mass index, smoking status and FEV1 (all ranges); (B) same covariates with
15 biomarkers; (C) covariates with FEV1 (≥ 50% predicted) and (D) covariates
with FEV1 (≥ 50% predicted) and 15 biomarkers.
ADIPOQ: Adiponectin; AGER/RAGE: Advanced glycosylation end products
receptor; AXL: AXL Receptor Tyrosine Kinase; CCL13: Monocyte chemotactic
protein 4; CCL2: Monocyte chemotactic protein 1; CCL20: Macrophage
inflammatory protein-3 alpha; CCL8: Monocyte chemotactic protein 2; CDH
13: Cadherin-13; CDH1: Cadherin-1; COPD: Chronic obstructive pulmonary
disease; CXCL10: Interferon gamma induced protein 10; FAS: FASLG receptor;
FEV1: Forced expiratory volume in first second; FVC: Forced vital capacity;
HRCT: High resolution computed tomography; HU: Hounsfield units;
ICAM1: Intercellular adhesion molecule 1; IgA: Immunoglobulin A;
IL-12B: Interleukin-12 Subunit p40; IL2RA: Interleukin-2 receptor alpha;
LAA: Low attenuation area; LLOQ: Lower limit of quantitation; LP15A: Mean
lung attenuation at the 15th percentile on lung attenuation curve;
MB: Myoglobin; MDA LDL: Malondialdehyde-modified low-density lipoprotein;
NRCAM: Neuronal cell adhesion molecule; SERPINA7: Thyroxin-binding globulin;
SFTPD: Surfactant protein D; SOD1: Superoxide dismutase 1; SORT1: Sortilin;
TGFB1 LAP: Latency-associated peptide of transforming growth factor beta 1;
TNFRSF11B: Osteoprotegerin.
Carolan et al. Respiratory Research 2014, 15:127
Competing interests
Dr. Carolan: The author has received lecture fees from Novartis. Dr. Hersh:
The author is a consultant for CSL Behring and receives lecture fees from
Novartis. Dr. Rennard: Entities with which SIR currently has relationships are
as follows: GlaxoSmithKline, Boehringer Ingelheim, Forest, AstraZeneca,
Chiesi, CME Incite, Takeda, Regeneron, Pearl, CIPLA, CSA, American Board of
Internal Medicine, Merck, Medimmune, Synapse, Nycomed, Dalichi Sankyo,
Novartis, Johnson and Johnson, Quadrant, Gerson Lehman, Able Associates,
CSL Behring, CTS Carmel, Decision Resources, FirstWord, Gilead, Guidepoint
Global, Pulmatrix, Saatchi and Saatchi, Schlesinger Associates, Cory Paeth,
Frankel Group, Medical Knowledge, Pro Ed Communication, LEX Consulting.
Dr. Belloni: The author is an employee of Genentech and receives stock or
stock options from Genentech/Roche. Dr. Comellas: The author is a
consultant for VIDA diagnostics. The other authors declare that they have no
competing interests.
Authors' contributions
BJC: Contributed to the data acquisition, analysis, and interpretation,
manuscript drafting and critical review for intellectual content and final
approval of the manuscript. BJC had full access to all of the data in the study
and takes responsibility for the integrity of the data and the accuracy of the
data analysis. GH: Contributed to the data analysis and interpretation, critical
review for important intellectual content and final approval of the
manuscript. JM: Contributed to the TESRA data analysis and interpretation.
CPH: Contributed to TESRA data acquisition, analysis and critical review for
the important intellectual content, and final approval of the manuscript.
WKO: Critical review for the important intellectual content and final approval
of the manuscript. SR: Critical review for the important intellectual content
and final approval of the manuscript. SGP: Contributed to TESRA data
acquisition, analysis and critical review for the important intellectual content,
and final approval of the manuscript. PB: Contributed to TESRA data
acquisition, analysis and critical review for the important intellectual content,
and final approval of the manuscript. DAC: Contributed to TESRA data
acquisition, analysis and critical review for the important intellectual content,
and final approval of the manuscript. APC: Contributed to data acquisition,
analysis and critical review for the important intellectual content and final
approval of the manuscript. MH: Critical review for the important intellectual
content and final approval of the manuscript. RLZ: Critical review for
important intellectual content and final approval of the manuscript KK:
Contributed to the data analysis and interpretation and drafting, critical
review for important intellectual content, and final approval of the
manuscript. RPB: Contributed to the study conception and design; data
analysis and interpretation; manuscript drafting, critical review for the
important intellectual content, and final approval of the manuscript.
All authors read and approved the final manuscript.
The authors would like to thank Sarah Hawthorne for editorial assistance.
Funding support
This study was supported by National Heart, Lung and Blood Institute (NHLBI
RO1HL 095432, U01 HL089856, U01 HL089897, P20 HL113445); UL1 RR025780
from NCRR/HIH and HHSN26820090020CP30 from NHLBI.
Author details
Department of Medicine, National Jewish Health, 1400 Jackson St, Denver,
CO 80206, USA. 2Department of Medicine, University of Colorado School of
Medicine, Aurora, CO, USA. 3Department of Biostatistics and Informatics,
Colorado School of Public Health, University of Colorado Denver, Aurora, CO,
USA. 4Channing Division of Network Medicine, Brigham and Women’s
Hospital and Harvard Medical School, Boston, MA, USA. 5Cystic Fibrosis/
Pulmonary Research and Treatment Center, Department of Medicine,
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 6Department
of Internal Medicine, Pulmonary, Critical Care and Allergy Division, University
of Nebraska Medical Center, Omaha, NE, USA. 7Hoffman La Roche, Nutley,
USA. 8Genentech, Member of the Roche Group, South San Francisco, CA,
USA. 9Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
Department of Internal Medicine, Division of Pulmonary and Critical Care,
University of Michigan Health System, Ann Arbor, MI, USA. 11Current address:
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA. 12Current
address: Boston Scientific, San Jose, CA, USA.
Page 9 of 10
Received: 29 May 2014 Accepted: 3 October 2014
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Cite this article as: Carolan et al.: The association of plasma biomarkers
with computed tomography-assessed emphysema phenotypes. Respiratory
Research 2014 15:127.
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