ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
Page 1 of 47
Lower leptin/adiponectin ratio and risk of rapid lung function decline in chronic obstructive pulmonary disease
Masaru Suzuki1, Hironi Makita1, Jörgen Östling2, Laura H. Thomsen3, Satoshi Konno1, Katsura Nagai1, Kaoruko Shimizu1, Jesper H. Pedersen4, Haseem Ashraf3,5, Piet L. B. Bruijnzeel2, Rose A. Maciewicz2, Masaharu Nishimura1, for the Hokkaido COPD cohort study and DLCST investigators
1
First Department of Medicine, Hokkaido University School of Medicine, Sapporo,
Japan 2
Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca
R&D, Mölndal, Sweden 3
Department of Respiratory Medicine, Gentofte Hospital, University of Copenhagen,
Hellerup, Denmark 4
Department of Cardiothoracic Surgery, Rigshospitalet, University of Copenhagen,
Copenhagen, Denmark 5
Department of Radiology, Akershus University Hospital, Loerenskog, Norway
Corresponding Author Masaharu Nishimura, M.D., Ph.D. First Department of Medicine, Hokkaido University School of Medicine North 15 West 7, Kita-ku, Sapporo 060-8638, Japan Tel: +81-11-706-5911; Fax: +81-11-706-7899; E-mail: [email protected]
Author Contributions: MS, statistical analysis, acquisition of data, interpretation of data, and drafting the manuscript; HM and MN, study concept and design, acquisition of data, interpretation
Copyright © 2014 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
of data, and finalizing of the manuscript; JÖ, statistical analysis, acquisition of data, interpretation of data; LHT, SK, KN, KS, JHP, HA, PLBB, and RAM, acquisition of data and interpretation of data.
Source of Support: The Hokkaido COPD cohort study was funded by a scientific research grant from the Ministry of Education, Science, Culture and Sports of Japan, a grant to the Respiratory Failure Research Group from the Ministry of Health, Labor and Welfare, Japan, Nippon Boehringer Ingelheim, Pfizer, and AstraZeneca. The DLCST study was funded in full by a grant from the Danish Ministry of Interior and Health.
Short Running Head: Lower leptin/adiponectin ratio in COPD
Subject Category: 9.13 COPD: Pathogenesis
Key Words: adipokines, biological markers, cohort studies
Total Word Count: 3,498
This article has a data supplement, which is accessible from this issue’s table of contents online at www.atsjournals.org
Copyright © 2014 by the American Thoracic Society
Page 2 of 47
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
Page 3 of 47
1
ABSTRACT
2
Rationale: The rate of annual change in forced expiratory volume in one second (FEV1)
3
is highly variable among patients with chronic obstructive pulmonary disease (COPD).
4
Reliable blood biomarkers are needed to predict prognosis.
5
Objectives: To explore plasma biomarkers associated with an annual change in FEV1 in
6
COPD patients.
7
Methods: Plasma samples of 261 subjects, all Japanese, with COPD from the 5-year
8
Hokkaido COPD cohort study were analyzed as a hypothesis-generating cohort, and the
9
results were validated using data of 226 subjects with and 268 subjects without airflow
10
limitation, mainly Caucasian, from the 4-year COPD quantification by Computed
11
Tomography (CT), Biomarkers and Quality of life (CBQ) study conducted in Denmark.
12
The plasma samples were measured using Human CardiovascularMAP® (Myriad RBM),
13
which could analyze 50 biomarkers potentially linked with inflammatory, metabolic,
14
and tissue remodeling pathways and single ELISAs were used to confirm the results.
15
Measurements and Main Results: Higher plasma adiponectin levels and a lower
16
leptin/adiponectin ratio at enrollment were significantly associated with an annual
17
decline in FEV1 even after controlling for age, sex, height, and body mass index in the
18
Hokkaido COPD cohort study (p=0.003, p=0.004, respectively). A lower plasma
19
leptin/adiponectin ratio was also significantly associated with an annual decline in FEV1
20
in subjects with airflow limitation in the CBQ study (p=0.014), the patients of which
21
had largely different clinical characteristics compared to the Hokkaido COPD cohort
22
study. There were no significant associations between lung function decline and
23
adipokine levels in subjects without airflow limitation.
24
Conclusions: A lower leptin/adiponectin ratio was associated with lung function decline
25
in patients with COPD in two independent Japanese and Western cohort studies of
26
populations of different ethnicity. Measure of systemic adipokines may provide utility in
27
predicting patients with COPD at higher risk of lung function decline.
1
Copyright © 2014 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
1 2
Abstract word count: 291
3
2
Copyright © 2014 by the American Thoracic Society
Page 4 of 47
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
Page 5 of 47
1 2
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is characterized by persistent
3
airflow limitation and is a leading cause of morbidity and mortality worldwide (1).
4
Recent prospective observational cohort studies have shown that the rate of annual
5
change in forced expiratory volume in one second (FEV1) is highly variable among
6
patients with COPD (2-4). In the Hokkaido COPD cohort study, it was found that higher
7
emphysema severity, higher blood neutrophil count, and lower blood eosinophil count
8
were associated with a rapid annual decline in FEV1 independent of baseline lung
9
function (2). Although several blood proteins such as club cell protein 16 have been
10
shown to be weakly associated with lung function decline in patients with COPD (5),
11
more reliable blood biomarkers are needed to predict patients’ prognosis. Any measure,
12
if it could be easily measured in routine clinical practice, might help reduce the burden
13
of COPD.
14
Adipokines are cytokines secreted mainly by adipose tissue, which include
15
adiponectin and leptin, and are associated with systemic inflammatory activities and
16
nutritional status (6). Blood adiponectin levels have been reported to be higher in
17
patients with COPD and to be associated with current emphysema severity and
18
exacerbation events (7-10). Therefore, dysregulation of adipokines could affect the
19
natural history of patients with COPD.
20
In this study, the aim was to explore plasma inflammatory and metabolic
21
mediators associated with the annual change in FEV1 in patients with COPD using a
22
multianalyte platform of biomarker candidates including adipokines. Data from the
23
Hokkaido COPD cohort study conducted in Japan were first analyzed as a
24
hypothesis-generating cohort. The results were then validated using data from the
25
COPD quantification by Computed Tomography (CT), Biomarkers and Quality of life
26
(CBQ) study conducted in Denmark recruited as part of the Danish Lung Cancer
27
Screening Trial (DLCST), in which the characteristics of the subjects were largely
3
Copyright © 2014 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
1
different from those of the Hokkaido COPD cohort in terms of age, sex, smoking status,
2
baseline lung function, and the rate of lung function decline. Some of the results of
3
these studies have been previously reported in the form of abstracts (11, 12).
4 5
METHODS
6
Hokkaido COPD cohort study
7
The Hokkaido COPD cohort study is a multi-center 5-year observational
8
cohort with 11 visits every 6 months (2, 13). In this study, 261 subjects who provided
9
blood (plasma) samples at enrollment (visit 1) were included for this analysis (Figure
10
E1 in the online supplement). The subjects’ characteristics are shown in Table 1.
11
Spirometry both before and after inhalation of a bronchodilator was performed on every
12
visit. The annual changes in post-bronchodilator FEV1 were obtained in 244 subjects
13
who had at least three spirometric measurements. Severity of emphysema on CT scan
14
was visually assessed by three independent pulmonologists (2, 13). Further details are
15
described in the online supplement.
16 17
DLCST/CBQ study
18
Participants were recruited from the DLCST, which is a single-center 4-year
19
trial with 5 visits investigating the effect of CT screening on lung cancer mortality (14,
20
15). All participants performed spirometry annually without inhalation of a
21
bronchodilator. A total of 1,812 subjects in the CT screening arm participated in a
22
substudy called the CBQ. Among them, 499 participants provided blood samples. Blood
23
samples were obtained in the third year (visit 3). In the current analysis, 268 subjects
24
without airflow limitation (FEV1/FVC ≥0.70) and 226 subjects with airflow limitation
25
(FEV1/FVC
Page 1 of 47
Lower leptin/adiponectin ratio and risk of rapid lung function decline in chronic obstructive pulmonary disease
Masaru Suzuki1, Hironi Makita1, Jörgen Östling2, Laura H. Thomsen3, Satoshi Konno1, Katsura Nagai1, Kaoruko Shimizu1, Jesper H. Pedersen4, Haseem Ashraf3,5, Piet L. B. Bruijnzeel2, Rose A. Maciewicz2, Masaharu Nishimura1, for the Hokkaido COPD cohort study and DLCST investigators
1
First Department of Medicine, Hokkaido University School of Medicine, Sapporo,
Japan 2
Respiratory, Inflammation and Autoimmunity Innovative Medicines, AstraZeneca
R&D, Mölndal, Sweden 3
Department of Respiratory Medicine, Gentofte Hospital, University of Copenhagen,
Hellerup, Denmark 4
Department of Cardiothoracic Surgery, Rigshospitalet, University of Copenhagen,
Copenhagen, Denmark 5
Department of Radiology, Akershus University Hospital, Loerenskog, Norway
Corresponding Author Masaharu Nishimura, M.D., Ph.D. First Department of Medicine, Hokkaido University School of Medicine North 15 West 7, Kita-ku, Sapporo 060-8638, Japan Tel: +81-11-706-5911; Fax: +81-11-706-7899; E-mail: [email protected]
Author Contributions: MS, statistical analysis, acquisition of data, interpretation of data, and drafting the manuscript; HM and MN, study concept and design, acquisition of data, interpretation
Copyright © 2014 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
of data, and finalizing of the manuscript; JÖ, statistical analysis, acquisition of data, interpretation of data; LHT, SK, KN, KS, JHP, HA, PLBB, and RAM, acquisition of data and interpretation of data.
Source of Support: The Hokkaido COPD cohort study was funded by a scientific research grant from the Ministry of Education, Science, Culture and Sports of Japan, a grant to the Respiratory Failure Research Group from the Ministry of Health, Labor and Welfare, Japan, Nippon Boehringer Ingelheim, Pfizer, and AstraZeneca. The DLCST study was funded in full by a grant from the Danish Ministry of Interior and Health.
Short Running Head: Lower leptin/adiponectin ratio in COPD
Subject Category: 9.13 COPD: Pathogenesis
Key Words: adipokines, biological markers, cohort studies
Total Word Count: 3,498
This article has a data supplement, which is accessible from this issue’s table of contents online at www.atsjournals.org
Copyright © 2014 by the American Thoracic Society
Page 2 of 47
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
Page 3 of 47
1
ABSTRACT
2
Rationale: The rate of annual change in forced expiratory volume in one second (FEV1)
3
is highly variable among patients with chronic obstructive pulmonary disease (COPD).
4
Reliable blood biomarkers are needed to predict prognosis.
5
Objectives: To explore plasma biomarkers associated with an annual change in FEV1 in
6
COPD patients.
7
Methods: Plasma samples of 261 subjects, all Japanese, with COPD from the 5-year
8
Hokkaido COPD cohort study were analyzed as a hypothesis-generating cohort, and the
9
results were validated using data of 226 subjects with and 268 subjects without airflow
10
limitation, mainly Caucasian, from the 4-year COPD quantification by Computed
11
Tomography (CT), Biomarkers and Quality of life (CBQ) study conducted in Denmark.
12
The plasma samples were measured using Human CardiovascularMAP® (Myriad RBM),
13
which could analyze 50 biomarkers potentially linked with inflammatory, metabolic,
14
and tissue remodeling pathways and single ELISAs were used to confirm the results.
15
Measurements and Main Results: Higher plasma adiponectin levels and a lower
16
leptin/adiponectin ratio at enrollment were significantly associated with an annual
17
decline in FEV1 even after controlling for age, sex, height, and body mass index in the
18
Hokkaido COPD cohort study (p=0.003, p=0.004, respectively). A lower plasma
19
leptin/adiponectin ratio was also significantly associated with an annual decline in FEV1
20
in subjects with airflow limitation in the CBQ study (p=0.014), the patients of which
21
had largely different clinical characteristics compared to the Hokkaido COPD cohort
22
study. There were no significant associations between lung function decline and
23
adipokine levels in subjects without airflow limitation.
24
Conclusions: A lower leptin/adiponectin ratio was associated with lung function decline
25
in patients with COPD in two independent Japanese and Western cohort studies of
26
populations of different ethnicity. Measure of systemic adipokines may provide utility in
27
predicting patients with COPD at higher risk of lung function decline.
1
Copyright © 2014 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
1 2
Abstract word count: 291
3
2
Copyright © 2014 by the American Thoracic Society
Page 4 of 47
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
Page 5 of 47
1 2
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is characterized by persistent
3
airflow limitation and is a leading cause of morbidity and mortality worldwide (1).
4
Recent prospective observational cohort studies have shown that the rate of annual
5
change in forced expiratory volume in one second (FEV1) is highly variable among
6
patients with COPD (2-4). In the Hokkaido COPD cohort study, it was found that higher
7
emphysema severity, higher blood neutrophil count, and lower blood eosinophil count
8
were associated with a rapid annual decline in FEV1 independent of baseline lung
9
function (2). Although several blood proteins such as club cell protein 16 have been
10
shown to be weakly associated with lung function decline in patients with COPD (5),
11
more reliable blood biomarkers are needed to predict patients’ prognosis. Any measure,
12
if it could be easily measured in routine clinical practice, might help reduce the burden
13
of COPD.
14
Adipokines are cytokines secreted mainly by adipose tissue, which include
15
adiponectin and leptin, and are associated with systemic inflammatory activities and
16
nutritional status (6). Blood adiponectin levels have been reported to be higher in
17
patients with COPD and to be associated with current emphysema severity and
18
exacerbation events (7-10). Therefore, dysregulation of adipokines could affect the
19
natural history of patients with COPD.
20
In this study, the aim was to explore plasma inflammatory and metabolic
21
mediators associated with the annual change in FEV1 in patients with COPD using a
22
multianalyte platform of biomarker candidates including adipokines. Data from the
23
Hokkaido COPD cohort study conducted in Japan were first analyzed as a
24
hypothesis-generating cohort. The results were then validated using data from the
25
COPD quantification by Computed Tomography (CT), Biomarkers and Quality of life
26
(CBQ) study conducted in Denmark recruited as part of the Danish Lung Cancer
27
Screening Trial (DLCST), in which the characteristics of the subjects were largely
3
Copyright © 2014 by the American Thoracic Society
ANNALSATS Articles in Press. Published on 05-November-2014 as 10.1513/AnnalsATS.201408-351OC
1
different from those of the Hokkaido COPD cohort in terms of age, sex, smoking status,
2
baseline lung function, and the rate of lung function decline. Some of the results of
3
these studies have been previously reported in the form of abstracts (11, 12).
4 5
METHODS
6
Hokkaido COPD cohort study
7
The Hokkaido COPD cohort study is a multi-center 5-year observational
8
cohort with 11 visits every 6 months (2, 13). In this study, 261 subjects who provided
9
blood (plasma) samples at enrollment (visit 1) were included for this analysis (Figure
10
E1 in the online supplement). The subjects’ characteristics are shown in Table 1.
11
Spirometry both before and after inhalation of a bronchodilator was performed on every
12
visit. The annual changes in post-bronchodilator FEV1 were obtained in 244 subjects
13
who had at least three spirometric measurements. Severity of emphysema on CT scan
14
was visually assessed by three independent pulmonologists (2, 13). Further details are
15
described in the online supplement.
16 17
DLCST/CBQ study
18
Participants were recruited from the DLCST, which is a single-center 4-year
19
trial with 5 visits investigating the effect of CT screening on lung cancer mortality (14,
20
15). All participants performed spirometry annually without inhalation of a
21
bronchodilator. A total of 1,812 subjects in the CT screening arm participated in a
22
substudy called the CBQ. Among them, 499 participants provided blood samples. Blood
23
samples were obtained in the third year (visit 3). In the current analysis, 268 subjects
24
without airflow limitation (FEV1/FVC ≥0.70) and 226 subjects with airflow limitation
25
(FEV1/FVC
