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1.  Peripheral blood gene expression profiles in COPD subjects 
To identify non-invasive gene expression markers for chronic obstructive pulmonary disease (COPD), we performed genome-wide expression profiling of peripheral blood samples from 12 subjects with significant airflow obstruction and an equal number of non-obstructed controls. RNA was isolated from Peripheral Blood Mononuclear Cells (PBMCs) and gene expression was assessed using Affymetrix U133 Plus 2.0 arrays.
Tests for gene expression changes that discriminate between COPD cases (FEV1< 70% predicted, FEV1/FVC < 0.7) and controls (FEV1> 80% predicted, FEV1/FVC > 0.7) were performed using Significance Analysis of Microarrays (SAM) and Bayesian Analysis of Differential Gene Expression (BADGE). Using either test at high stringency (SAM median FDR = 0 or BADGE p < 0.01) we identified differential expression for 45 known genes. Correlation of gene expression with lung function measurements (FEV1 & FEV1/FVC), using both Pearson and Spearman correlation coefficients (p < 0.05), identified a set of 86 genes. A total of 16 markers showed evidence of significant correlation (p < 0.05) with quantitative traits and differential expression between cases and controls. We further compared our peripheral gene expression markers with those we previously identified from lung tissue of the same cohort. Two genes, RP9and NAPE-PLD, were identified as decreased in COPD cases compared to controls in both lung tissue and blood. These results contribute to our understanding of gene expression changes in the peripheral blood of patients with COPD and may provide insight into potential mechanisms involved in the disease.
PMCID: PMC3164605  PMID: 21884629
Microarray; Biomarkers; PBMC
2.  Differential Expression of Tissue Repair Genes in the Pathogenesis of Chronic Obstructive Pulmonary Disease 
Rationale: The airflow limitation that defines severity of chronic obstructive pulmonary disease (COPD) is caused by a combination of small airway obstruction and emphysematous lung destruction.
Objectives: To examine the hypothesis that small airway obstructive and emphysematous destructive lesions are produced by differential expression of genes associated with tissue repair.
Methods: The expression of 54 genes associated with repair of repetitively damaged tissue was measured in 136 paired samples of small bronchioles and surrounding lung tissue separated by laser capture microdissection. These samples were collected from 63 patients at different levels of disease severity who required surgery for either lung cancer or lung transplantation for very severe COPD. Gene expression was measured by quantitative polymerase chain reaction in these paired samples and compared with the FEV1 by linear regression analysis.
Measurements and Main Results: After corrections for false discovery rates, only 2 of 10 genes (serpin peptidase inhibitor/plasminogen activator inhibitor member 2 and matrix metalloproteinase [MMP] 10) increased, whereas 8 (MMP2, integrin-α1, vascular endothelial growth factor, a disintegrin and metallopeptidase domain 33, scatter factor/hepatocyte growth factor, tissue inhibitor of matrix metalloproteinase-2, fibronectin, and collagen 3α1) decreased in small airways in association with FEV1. In contrast, 8/12 genes (early growth response factor 1, MMP1, MMP9, MMP10, plasminogen activator urokinase, plasminogen activator urokinase receptor, tumor necrosis factor, and IL13) increased and 4/12 (MMP2, tissue inhibitor of matrix metalloproteinase-1, collagen 1α1, and transforming growth factor-β3) decreased in the surrounding lung tissue in association with progression of COPD.
Conclusions: The progression of COPD is associated with the differential expression of a cluster of genes that favor the degradation of the tissue surrounding the small conducting airways.
PMCID: PMC2894408  PMID: 20075389
emphysema; pulmonary disease, chronic obstructive; polymerase chain reaction; laser microdissection; nucleic acid amplification techniques
3.  Genome-Wide Association Studies Identify CHRNA5/3 and HTR4 in the Development of Airflow Obstruction 
Wilk, Jemma B. | Shrine, Nick R. G. | Loehr, Laura R. | Zhao, Jing Hua | Manichaikul, Ani | Lopez, Lorna M. | Smith, Albert Vernon | Heckbert, Susan R. | Smolonska, Joanna | Tang, Wenbo | Loth, Daan W. | Curjuric, Ivan | Hui, Jennie | Cho, Michael H. | Latourelle, Jeanne C. | Henry, Amanda P. | Aldrich, Melinda | Bakke, Per | Beaty, Terri H. | Bentley, Amy R. | Borecki, Ingrid B. | Brusselle, Guy G. | Burkart, Kristin M. | Chen, Ting-hsu | Couper, David | Crapo, James D. | Davies, Gail | Dupuis, Josée | Franceschini, Nora | Gulsvik, Amund | Hancock, Dana B. | Harris, Tamara B. | Hofman, Albert | Imboden, Medea | James, Alan L. | Khaw, Kay-Tee | Lahousse, Lies | Launer, Lenore J. | Litonjua, Augusto | Liu, Yongmei | Lohman, Kurt K. | Lomas, David A. | Lumley, Thomas | Marciante, Kristin D. | McArdle, Wendy L. | Meibohm, Bernd | Morrison, Alanna C. | Musk, Arthur W. | Myers, Richard H. | North, Kari E. | Postma, Dirkje S. | Psaty, Bruce M. | Rich, Stephen S. | Rivadeneira, Fernando | Rochat, Thierry | Rotter, Jerome I. | Artigas, María Soler | Starr, John M. | Uitterlinden, André G. | Wareham, Nicholas J. | Wijmenga, Cisca | Zanen, Pieter | Province, Michael A. | Silverman, Edwin K. | Deary, Ian J. | Palmer, Lyle J. | Cassano, Patricia A. | Gudnason, Vilmundur | Barr, R. Graham | Loos, Ruth J. F. | Strachan, David P. | London, Stephanie J. | Boezen, H. Marike | Probst-Hensch, Nicole | Gharib, Sina A. | Hall, Ian P. | O’Connor, George T. | Tobin, Martin D. | Stricker, Bruno H.
Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations.
Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
PMCID: PMC3480517  PMID: 22837378
chronic obstructive pulmonary disease; single-nucleotide polymorphism; genes
4.  Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity 
Thorax  2013;69(1):14-23.
A core feature of chronic obstructive pulmonary disease (COPD) is the accelerated decline in forced expiratory volume in one second (FEV1). The recent Groningen and Leiden Universities study of Corticosteroids in Obstructive Lung Disease (GLUCOLD) study suggested that particular phenotypes of COPD benefit from fluticasone±salmeterol by reducing the rate of FEV1 decline, yet the underlying mechanisms are unknown.
Whole-genome gene expression profiling using the Affymetrix Gene ST array (V.1.0) was performed on 221 bronchial biopsies available from 89 COPD patients at baseline and after 6 and 30 months of fluticasone±salmeterol and placebo treatment in GLUCOLD.
Linear mixed effects modelling revealed that the expression of 138 genes decreased, whereas the expression of 140 genes significantly upregulated after both 6 and 30 months of treatment with fluticasone±salmeterol versus placebo. A more pronounced treatment-induced change in the expression of 50 and 55 of these 278 genes was associated with a lower rate of decline in FEV1 and Saint George Respiratory Questionnaire, respectively. Genes decreasing with treatment were involved in pathways related to cell cycle, oxidative phosphorylation, epithelial cell signalling, p53 signalling and T cell signalling. Genes increasing with treatment were involved in pathways related to focal adhesion, gap junction and extracellular matrix deposition. Finally, the fluticasone-induced gene expression changes were enriched among genes that change in the airway epithelium in smokers with versus without COPD in an independent data set.
The present study suggests that gene expression in biological pathways of COPD is dynamic with treatment and reflects disease activity. This study opens the gate to targeted and molecular phenotype-driven therapy of COPD.
PMCID: PMC3888587  PMID: 23925644
COPD ÀÜ Mechanisms
5.  Inverse association of plasma IL-13 and inflammatory chemokines with lung function impairment in stable COPD: a cross-sectional cohort study 
Respiratory Research  2007;8(1):64.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by varying degrees of airflow limitation and diffusion impairment. There is increasing evidence to suggest that COPD is also characterized by systemic inflammation. The primary goal of this study was to identify soluble proteins in plasma that associate with the severity of airflow limitation in a COPD cohort with stable disease. A secondary goal was to assess whether unique markers associate with diffusion impairment, based on diffusion capacity of carbon monoxide (DLCO), independent of the forced expiratory volume in 1 second (FEV1).
A cross sectional study of 73 COPD subjects was performed in order to examine the association of 25 different plasma proteins with the severity of lung function impairment, as defined by the baseline measurements of the % predicted FEV1 and the % predicted DLCO. Plasma protein concentrations were assayed using multiplexed immunobead-based cytokine profiling. Associations between lung function and protein concentrations were adjusted for age, gender, pack years smoking history, current smoking, inhaled corticosteroid use, systemic corticosteroid use and statin use.
Plasma concentrations of CCL2/monocyte chemoattractant protein-1 (CCL2/MCP-1), CCL4/macrophage inflammatory protein-1β (CCL4/MIP -1β), CCL11/eotaxin, and interleukin-13 (IL-13) were inversely associated with the % FEV1. Plasma concentrations of soluble Fas were associated with the % DLCO, whereas CXCL9/monokine induced by interferon-γ (CXCL9/Mig), granulocyte- colony stimulating factor (G-CSF) and IL-13 showed inverse relationships with the % DLCO.
Systemic inflammation in a COPD cohort is characterized by cytokines implicated in inflammatory cell recruitment and airway remodeling. Plasma concentrations of IL-13 and chemoattractants for monocytes, T lymphocytes, and eosinophils show associations with increasing severity of disease. Soluble Fas, G-CSF and CXCL9/Mig may be unique markers that associate with disease characterized by disproportionate abnormalities in DLCO independent of the FEV1.
PMCID: PMC2064925  PMID: 17868461
6.  Identification of Clinical Phenotypes Using Cluster Analyses in COPD Patients with Multiple Comorbidities 
BioMed Research International  2014;2014:420134.
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, the severity of which is assessed using forced expiratory volume in 1 sec (FEV1, % predicted). Cohort studies have confirmed that COPD patients with similar levels of airflow limitation showed marked heterogeneity in clinical manifestations and outcomes. Chronic coexisting diseases, also called comorbidities, are highly prevalent in COPD patients and likely contribute to this heterogeneity. In recent years, investigators have used innovative statistical methods (e.g., cluster analyses) to examine the hypothesis that subgroups of COPD patients sharing clinically relevant characteristics (phenotypes) can be identified. The objectives of the present paper are to review recent studies that have used cluster analyses for defining phenotypes in observational cohorts of COPD patients. Strengths and weaknesses of these statistical approaches are briefly described. Description of the phenotypes that were reasonably reproducible across studies and received prospective validation in at least one study is provided, with a special focus on differences in age and comorbidities (including cardiovascular diseases). Finally, gaps in current knowledge are described, leading to proposals for future studies.
PMCID: PMC3934315
7.  Comparison of the Prevalence of Chronic Obstructive Pulmonary Disease Diagnosed by Lower Limit of Normal and Fixed Ratio Criteria 
Journal of Korean Medical Science  2009;24(4):621-626.
The Global Initiative of Chronic Obstructive Lung Disease (GOLD) guidelines define chronic obstructive pulmonary disease (COPD) in subjects with FEV1/FVC <0.7. However, the use of this fixed ratio may result in over-diagnosis of COPD in the elderly, especially with mild degree of COPD. The lower limit of normal (LLN) can be used to minimize the potential misclassification. The aim of this study was to evaluate the impact of different definitions of airflow obstruction (LLN or fixed ratio of FEV1/FVC) on the estimated prevalence of COPD in a population-based sample. We compared the prevalence of COPD and its difference diagnosed by different methods using either fixed ratio (FEV1/FVC <0.7) or LLN criterion (FEV1/FVC below LLN). Among the 4,816 subjects who had performed spirometry, 2,728 subjects met new ATS/ERS spirometry criteria for acceptability and repeatability. The prevalence of COPD was 10.9% (14.7% in men, 7.2% in women) by LLN criterion and 15.5% (21.8% in men, 9.1% in women) by fixed ratio of FEV1/FVC among subjects older than 45 yr. The difference of prevalence between LLN and fixed ratio of FEV1/FVC was even higher among subjects with age ≥65, 14.9% and 31.1%, respectively. In conclusion, the prevalence of COPD by LLN criterion was significantly lower in elderly compared to fixed ratio of FEV1/FVC. Implementing LLN criterion instead of fixed ratio of FEV1/FVC may reduce the risk of over-diagnosis of COPD in elderly people.
PMCID: PMC2719218  PMID: 19654942
Pulmonary Disease, Chronic Obstructive; National Prevalence; Lower Limit of Normal; Spirometry
8.  Gene expression profiles of alveolar type II cells of chronic obstructive pulmonary disease: a case–control study 
BMJ Open  2012;2(6):e001553.
The aim of this study was to identify the gene expression pattern specific in alveolar epithelial type II cells (ATII cells) isolated from patients with chronic obstructive pulmonary disease (COPD).
Case control.
Two hospitals in Japan.
Three patients without COPD and three patients with COPD in microarray analyses. Five smokers without COPD and nine smokers with COPD in the following analyses.
Primary and secondary outcome measured
Primary outcome included identification of differentially expressed genes and activated or inhibited pathways in ATII cells of the patients with COPD, compared to those of the patients without COPD, using Affymetrix gene expression arrays. Secondary outcome included validation of the results of microarray analyses by quantitative reverse transcription-PCR.
We isolated ATII cells from COPD and non-COPD lungs using fluorescence-activated cell sorting. We performed Affymetrix gene expression arrays on both types of ATII cells. Gene set enrichment analyses revealed that two major gene sets were enriched in ATII cells from COPD lungs: interferon-responsive gene sets and gene sets associated with cell cycle progression. Gene ontology term enrichment analyses indicated that among the interferon-stimulated genes, ATII cells in COPD expressed genes such as PSMB8, PSMB9, TAP1 and TAP2 associated with the antigen processing and presentation pathway. We validated the results of the microarray analyses using quantitative reverse transcriptase-PCR. In addition, FACS analysis indicated that the percentage of ATII cells to CD45-negative lung cells isolated from COPD lungs were significantly increased more than that from non-COPD lungs.
Our study demonstrated that interferon-stimulated genes involved in the antigen processing and presentation pathway and genes involved in cell cycle progression were enriched in ATII cells of the patients with COPD. These pathways might alter phenotypes of ATII cells in COPD lungs.
PMCID: PMC3532994  PMID: 23117565
Molecular Biology; Respiratory Medicine (see Thoracic Medicine)
9.  Morphological measurements in computed tomography correlate with airflow obstruction in chronic obstructive pulmonary disease: systematic review and meta-analysis 
European Radiology  2012;22(10):2085-2093.
To determine the correlation between CT measurements of emphysema or peripheral airways and airflow obstruction in chronic obstructive pulmonary disease (COPD).
PubMed, Embase and Web of Knowledge were searched from 1976 to 2011. Two reviewers independently screened 1,763 citations to identify articles that correlated CT measurements to airflow obstruction parameters of the pulmonary function test in COPD patients, rated study quality and extracted information. Three CT measurements were accessed: lung attenuation area percentage < -950 Hounsfield units, mean lung density and airway wall area percentage. Two airflow obstruction parameters were accessed: forced expiratory volume in the first second as percentage from predicted (FEV1 %pred) and FEV1 divided by the forced volume vital capacity.
Seventy-nine articles (9,559 participants) were included in the systematic review, demonstrating different methodologies, measurements and CT airflow obstruction correlations. There were 15 high-quality articles (2,095 participants) in the meta-analysis. The absolute pooled correlation coefficients ranged from 0.48 (95 % CI, 0.40 to 0.54) to 0.65 (0.58 to 0.71) for inspiratory CT and 0.64 (0.53 to 0.72) to 0.73 (0.63 to 0.80) for expiratory CT.
CT measurements of emphysema or peripheral airways are significantly related to airflow obstruction in COPD patients. CT provides a morphological method to investigate airway obstruction in COPD.
Key Points
• Computed tomography is widely performed in patients with chronic obstructive pulmonary disease (COPD)
• CT provides quantitative morphological methods to investigate airflow obstruction in COPD
• CT measurements correlate significantly with the degree of airflow obstruction in COPD
• Expiratory CT measurements correlate more strongly with airflow obstruction than inspiratory CT
• Low-dose CT decreases the radiation dose for diagnosis and quantitative emphysema evaluation
Electronic supplementary material
The online version of this article (doi:10.1007/s00330-012-2480-8) contains supplementary material, which is available to authorized users.
PMCID: PMC3431473  PMID: 22699870
Review, systematic; Meta-analysis; Tomography, X-ray computed; Pulmonary disease, chronic obstructive; Function test, pulmonary
10.  Lung function decline in COPD 
The landmark study of Fletcher and Peto on the natural history of tobacco smoke-related chronic airflow obstruction suggested that decline in the forced expiratory volume in the first second (FEV1) in chronic obstructive pulmonary disease (COPD) is slow at the beginning, becoming faster with more advanced disease. The present authors reviewed spirometric data of COPD patients included in the placebo arms of recent clinical trials to assess the lung function decline of each stage, defined according to the severity of airflow obstruction as proposed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. In large COPD populations the mean rate of FEV1 decline in GOLD stages II and III is between 47 and 79 mL/year and 56 and 59 mL/year, respectively, and lower than 35 mL/year in GOLD stage IV. Few data on FEV1 decline are available for GOLD stage I. Hence, the loss of lung function, assessed as expiratory airflow reduction, seems more accelerated and therefore more relevant in the initial phases of COPD. To have an impact on the natural history of COPD, it is logical to look at the effects of treatment in the earlier stages.
PMCID: PMC3282601  PMID: 22371650
chronic obstructive pulmonary disease; decline; forced expiratory volume in 1 second; FEV1
11.  A new staging strategy for chronic obstructive pulmonary disease 
The best method for expressing lung function impairment is undecided. We tested in a population of patients with chronic obstructive pulmonary disease (COPD) whether forced expiratory volume in 1 second (FEV1) or FEV1 divided by height squared (FEV1/ht2) was better than FEV1 percent predicted (FEV1PP) for predicting survival.
FEV1, FEV1PP, and FEV1/ht2 recorded post bronchodilator were compared as predictors of survival in 1095 COPD patients followed for 15 years. A staging system for severity of COPD was defined from FEV1/ht2 and compared with the Global Initiative for Obstructive Lung Disease (GOLD) staging system.
FEV1/ht2 was a better univariate predictor of survival in COPD than FEV1 and both were better than FEV1PP. The best multivariate model for predicting survival included FEV1/ht2, age and sex. Comparing the GOLD stages with the FEV1/ht2 groups found that survival was more coherent within each FEV1/ht group than it was within each GOLD stage. FEV1/ht2 had 60% more people in its most severe group than the severest GOLD stage with these extra subjects having equivalently poor survival and had 155% more in the least severe group with equivalent survival. GOLD staging misclassified 51% of subjects with regard to survival.
We conclude that GOLD criteria using FEV1PP do not optimally stage COPD with regard to survival. An alternative strategy using FEV1/ht2 improves the staging of this disease. Studies which stratify COPD patients to determine the effect of interventions such as drug trials, rehabilitation, or management guidelines should consider alternatives to the GOLD classification.
PMCID: PMC2699963  PMID: 18268941
chronic obstructive pulmonary disease; spirometry; respiratory function tests
12.  Genes and Gene Ontologies Common to Airflow Obstruction and Emphysema in the Lungs of Patients with COPD 
PLoS ONE  2011;6(3):e17442.
Chronic obstructive pulmonary disease (COPD) is a major public health problem with increasing prevalence worldwide. The primary aim of this study was to identify genes and gene ontologies associated with COPD severity. Gene expression profiling was performed on total RNA extracted from lung tissue of 18 former smokers with COPD. Class comparison analysis on mild (n = 9, FEV1 80–110% predicted) and moderate (n = 9, FEV1 50–60% predicted) COPD patients identified 46 differentially expressed genes (p<0.01), of which 14 genes were technically confirmed by quantitative real-time-PCR. Biological replication in an independent test set of 58 lung samples confirmed the altered expression of ten genes with increasing COPD severity, with eight of these genes (NNMT, THBS1, HLA-DPB1, IGHD, ETS2, ELF1, PTGDS and CYRBD1) being differentially expressed by greater than 1.8 fold between mild and moderate COPD, identifying these as candidate determinants of COPD severity. These genes belonged to ontologies potentially implicated in COPD including angiogenesis, cell migration, proliferation and apoptosis. Our secondary aim was to identify gene ontologies common to airway obstruction, indicated by impaired FEV1 and KCO. Using gene ontology enrichment analysis we have identified relevant biological and molecular processes including regulation of cell-matrix adhesion, leukocyte activation, cell and substrate adhesion, cell adhesion, angiogenesis, cell activation that are enriched among genes involved in airflow obstruction. Exploring the functional significance of these genes and their gene ontologies will provide clues to molecular changes involved in severity of COPD, which could be developed as targets for therapy or biomarkers for early diagnosis.
PMCID: PMC3057973  PMID: 21423603
13.  Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease 
Thorax  2012;68(7):670-676.
Chronic obstructive pulmonary disease (COPD) is a multicomponent condition that is characterised by airflow obstruction that is not fully reversible and is a major global cause of morbidity and mortality. The most widely used marker of disease severity and progression is FEV1. However, FEV1 correlates poorly with both symptoms and other measures of disease progression and thus there is an urgent need for other biological markers to better characterise individuals with COPD. Fibrinogen is an acute phase plasma protein that has emerged as a promising biomarker in COPD. Here we review the current clinical evidence linking fibrinogen with COPD and its associated co-morbidities and discuss its potential utility as a biomarker.
Searches for appropriate studies were undertaken on PubMed using search terms fibrinogen, COPD, emphysema, chronic bronchitis, FEV1, cardiovascular disease, exacerbation and mortality.
There is strong evidence of an association between fibrinogen and the presence of COPD, the presence and frequency of exacerbations and with mortality. Fibrinogen is associated with disease severity but does not predict lung function decline, a measure used as a surrogate for disease activity. The role of fibrinogen in identifying inflammatory co morbidities, particularly cardiovascular disease, remains unclear. Fibrinogen is reduced by p38 mitogen-activated protein kinase inhibitors in individuals with stable disease and by oral corticosteroids during exacerbations.
Fibrinogen is likely to be a useful biomarker to stratify individuals with COPD into those with a high or low risk of future exacerbations and may identify those with a higher risk of mortality.
PMCID: PMC3711372  PMID: 22744884
Fibrinogen; inflammation; COPD; biomarker
14.  The Influence of Radiographic Phenotype and Smoking Status on Peripheral Blood Biomarker Patterns in Chronic Obstructive Pulmonary Disease 
PLoS ONE  2009;4(8):e6865.
Chronic obstructive pulmonary disease (COPD) is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD.
Methodology/Principal Findings
Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1%) and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status.
Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies.
PMCID: PMC2730536  PMID: 19718453
15.  Lung Function in Young Adults Predicts Airflow Obstruction 20 Years Later 
The American journal of medicine  2010;123(5):468.e1-468.e7.
The burden of obstructive lung disease is increasing, yet there are limited data on its natural history in young adults.
To determine in a prospective cohort of generally healthy young adults the influence of early adult lung function on the presence of airflow obstruction in middle age.
Longitudinal study of 2,496 adults who were 18-30 years of age at entry, did not report having asthma, and returned at Year 20. Airflow obstruction was defined as an FEV1/FVC ratio less than the lower limit of normal.
Measurements and Main Results
Airflow obstruction was present in 6.9% and 7.8% of participants at Years 0 and 20. Less than 10% of participants with airflow obstruction self-reported COPD. In cross sectional analyses airflow obstruction was associated with less education, smoking, and self-reported COPD. Low FEV1 and FEV1/FVC and airflow obstruction in young adults were associated with low lung function and airflow obstruction 20 years later. Of those with airflow obstruction at Year 0, 52% had airflow obstruction 20 years later. The FEV1/FVC at Year 0 was highly predictive of airflow obstruction 20 years later (c-statistic 0.91; 95% CI 0.89-0.93). The effect of cigarette smoking on lung function decline with age was most evident in young adults with pre-existing airflow obstruction.
Airflow obstruction is mostly unrecognized in young and middle age adults. A low FEV1, low FEV1/FVC and airflow obstruction in young adults, in addition to smoking, are highly predictive of low lung function and airflow obstruction in middle age.
PMCID: PMC2858051  PMID: 20399325
Airflow obstruction; CARDIA; chronic obstructive pulmonary disease; COPD; natural history
16.  IL10 Polymorphisms Are Associated with Airflow Obstruction in Severe α1-Antitrypsin Deficiency 
Severe α1-antitrypsin (AAT) deficiency is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD), especially in individuals who smoke. There is marked variability in the development of lung disease in individuals homozygous (PI ZZ) for this autosomal recessive condition, suggesting that modifier genes could be important. We hypothesized that genetic determinants of obstructive lung disease may be modifiers of airflow obstruction in individuals with severe AAT deficiency. To identify modifier genes, we performed family-based association analyses for 10 genes previously associated with asthma and/or COPD, including IL10, TNF, GSTP1, NOS1, NOS3, SERPINA3, SERPINE2, SFTPB, TGFB1, and EPHX1. All analyses were performed in a cohort of 378 PI ZZ individuals from 167 families. Quantitative spirometric phenotypes included forced expiratory volume in one second (FEV1) and the ratio of FEV1/forced vital capacity (FVC). A qualitative phenotype of moderate-to-severe COPD was defined for individuals with FEV1 ⩽ 50 percent predicted. Six of 11 single-nucleotide polymorphisms (SNPs) in IL10 (P = 0.0005–0.05) and 3 of 5 SNPs in TNF (P = 0.01–0.05) were associated with FEV1 and/or FEV1/FVC. IL10 SNPs also demonstrated association with the qualitative COPD phenotype. When phenotypes of individuals with a physician's diagnosis of asthma were excluded, IL10 SNPs remained significantly associated, suggesting that the association with airflow obstruction was independent of an association with asthma. Haplotype analysis of IL10 SNPs suggested the strongest association with IL10 promoter SNPs. IL10 is likely an important modifier gene for the development of COPD in individuals with severe AAT deficiency.
PMCID: PMC2176135  PMID: 17690329
chronic obstructive pulmonary disease; genetic modifiers; interleukin 10; family-based association analysis
17.  Proportional classifications of COPD phenotypes 
Thorax  2008;63(9):761-767.
Chronic obstructive pulmonary disease (COPD) encompasses a group of disorders characterised by the presence of incompletely reversible airflow obstruction with overlapping subsets of different phenotypes including chronic bronchitis, emphysema or asthma. The aim of this study was to determine the proportion of adult subjects aged >50 years within each phenotypic subgroup of COPD, defined as a post-bronchodilator ratio of forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.7, in accordance with current international guidelines.
Adults aged >50 years derived from a random population-based survey undertook detailed questionnaires, pulmonary function tests and chest CT scans. The proportion of subjects in each of 16 distinct phenotypes was determined based on combinations of chronic bronchitis, emphysema and asthma, with and without incompletely reversible airflow obstruction defined by a post-bronchodilator FEV1/FVC ratio of 0.7.
A total of 469 subjects completed the investigative modules, 96 of whom (20.5%) had COPD. Diagrams were constructed to demonstrate the relative proportions of the phenotypic subgroups in subjects with and without COPD. 18/96 subjects with COPD (19%) had the classical phenotypes of chronic bronchitis and/or emphysema but no asthma; asthma was the predominant COPD phenotype, being present in 53/96 (55%). When COPD was defined as a post-bronchodilator FEV1/FVC less than the lower limit of normal, there were one-third fewer subjects with COPD and a smaller proportion without a defined emphysema, chronic bronchitis or asthma phenotype.
This study provides proportional classifications of the phenotypic subgroups of COPD which can be used as the basis for further research into the pathogenesis and treatment of this heterogeneous disorder.
PMCID: PMC2862964  PMID: 18728201
18.  Physiological and radiological characterisation of patients diagnosed with chronic obstructive pulmonary disease in primary care 
Thorax  2000;55(8):635-642.
BACKGROUND—Chronic obstructive pulmonary disease (COPD) is common although often poorly characterised, particularly in primary care. However, application of guidelines to the management of such patients needs a clear understanding of the phenotype. In particular, the British guidelines for the management of COPD recommend that the diagnosis is based on appropriate symptoms and evidence of airflow obstruction as determined by a forced expiratory volume in one second (FEV1) of <80% of the predicted value and an FEV1/VC ratio of <70%.
METHODS—A study was undertaken of 110 patients aged 40-80 years who had presented to their general practitioner with an acute exacerbation of COPD. The episode was treated at home and, when patients had recovered to the stable state (two months later), they were characterised by full lung function tests and a high resolution computed tomographic (HRCT) scan of the chest.
RESULTS—There was a wide range of impairment of FEV1 which was in the normal range (⩾80%) in 30%, mildly impaired (60-79%) in 18%, moderately impaired (40-59%) in 33%, and severely impaired (<40%) in 19% of patients. A reduced FEV1/VC ratio was present in all patients with an FEV1 of <80% predicted but also in 41% of those with an FEV1 of ⩾80% predicted. Only 5% of patients had a substantial bronchodilator response suggesting a diagnosis of asthma. Emphysema was present in 51% of patients and confined to the upper lobes in most (73% of these patients). HRCT evidence of bronchiectasis was noted in 29% of patients and was predominantly tubular; most (81%) were current or ex-smokers. A solitary pulmonary nodule was seen on 9% of scans and unsuspected lung malignancy was diagnosed in two patients.
CONCLUSIONS—This study confirms that COPD in primary care is a heterogeneous condition. Some patients do not fulfil the proposed diagnostic criteria with FEV1 of ⩾80% predicted but they may nevertheless have airflow obstruction. Bronchiectasis is common in this group of patients, as is unsuspected malignancy. These findings should be considered when developing recommendations for the investigation and management of COPD in the community.

PMCID: PMC1745831  PMID: 10899238
19.  Tenascin-C and alpha-smooth muscle actin positive cells are increased in the large airways in patients with COPD 
Respiratory Research  2011;12(1):48.
Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and remodeling of the lungs. This results in alterations in extracellular matrix (ECM) and structural changes leading to airflow obstruction. We studied the expression of tenascin-C (Tn-C) and alpha smooth muscle actin (α-SMA), which act as a marker of myofibroblasts, in large airways from COPD patients. Our aim was to elucidate whether this expression correlated with smoking or with disease development.
Bronchoscopy was performed on 20 COPD patients (mean age 56 years; range 39-61; FEV1/FVC < 70% and FEV1 median 53% (range 33-69) of predicted). Age and smoking matched smokers (S) without COPD (n = 13) and age matched non-smokers (NS) (n = 14) served as controls. Bronchial mucosal biopsies were analyzed by immunohistochemistry. The distribution of Tn-C expression was assessed and graded in three levels, and the number of spindle shaped cells staining positive for α-SMA were counted.
Biopsies from COPD patients had more (P < 0.001) Tn-C expression than the two control groups. A significantly (P < 0.05) increased number of spindle shaped cells expressing α-SMA was observed in COPD patients compared with the controls. Smokers and nonsmokers did not differ in this respect. The expression of Tn-C correlated positively (P < 0.001) to the number of α-SMA positive cells.
We demonstrate increased expression of Tn-C and α-SMA positive cells in the large airways in COPD. This was not associated to smoking per se, but to the presence of airway obstruction. Our findings add new information regarding remodeling characteristics and highlight the large airways as a potential site for airways obstruction in COPD.
PMCID: PMC3083344  PMID: 21496259
20.  Pathogenic triad in COPD: oxidative stress, protease–antiprotease imbalance, and inflammation 
Patients with chronic obstructive pulmonary disease (COPD) exhibit dominant features of chronic bronchitis, emphysema, and/or asthma, with a common phenotype of airflow obstruction. COPD pulmonary physiology reflects the sum of pathological changes in COPD, which can occur in large central airways, small peripheral airways, and the lung parenchyma. Quantitative or high-resolution computed tomography is used as a surrogate measure for assessment of disease progression. Different biological or molecular markers have been reported that reflect the mechanistic or pathogenic triad of inflammation, proteases, and oxidants and correspond to the different aspects of COPD histopathology. Similar to the pathogenic triad markers, genetic variations or polymorphisms have also been linked to COPD-associated inflammation, protease–antiprotease imbalance, and oxidative stress. Furthermore, in recent years, there have been reports identifying aging-associated mechanistic markers as downstream consequences of the pathogenic triad in the lungs from COPD patients. For this review, the authors have limited their discussion to a review of mechanistic markers and genetic variations and their association with COPD histopathology and disease status.
PMCID: PMC3157944  PMID: 21857781
senescence; apoptosis; chronic obstructive pulmonary disease; bronchitis; emphysema
21.  Gender Differences in Plasma Biomarker Levels in a Cohort of COPD Patients: A Pilot Study 
PLoS ONE  2011;6(1):e16021.
Little is known about gender differences in plasma biomarker levels in patients with chronic obstructive pulmonary disease (COPD).
There are differences in serum biomarker levels between women and men with COPD.
Explore gender differences in plasma biomarker levels in patients with COPD and smokers without COPD.
We measured plasma levels of IL-6, IL-8, IL-16, MCP-1, MMP-9, PARC and VEGF in 80 smokers without COPD (40 males, 40 females) and 152 stable COPD patients (76 males, 76 females) with similar airflow obstruction. We determined anthropometrics, smoking history, lung function, exercise tolerance, body composition, BODE index, co-morbidities and quality of life. We then explored associations between plasma biomarkers levels and the clinical characteristics of the patients and also with the clinical and physiological variables known to predict outcome in COPD.
The plasma biomarkers level explored were similar in men and women without COPD. In contrast, in patients with COPD the median value in pg/mL of IL-6 (6.26 vs 8.0, p = 0.03), IL-16 (390 vs 321, p = 0.009) and VEGF (50 vs 87, p = 0.02) differed between women and men. Adjusted for smoking history, gender was independently associated with IL-16, PARC and VEGF levels. There were also gender differences in the associations between IL-6, IL-16 and VEGF and physiologic variables that predict outcomes.
In stable COPD patients with similar airflow obstruction, there are gender differences in plasma biomarker levels and in the association between biomarker levels and important clinical or physiological variables. Further studies should confirm our findings.
PMCID: PMC3022655  PMID: 21267454
The European respiratory journal  2007;30(2):232-239.
A recent ATS and ERS joint taskforce report recommends using a lower limit of normal (LLN) of FEV1/FVC as opposed to a fixed ratio of <0.7 to diagnose airflow obstruction, to reduce false positive diagnoses of COPD as defined by the Global Initiative for Obstructive Lung Disease (GOLD). To date there is no reliable spirometry-based prevalence data for COPD in New Zealand and the effect of different definitions of airflow obstruction based on post-bronchodilator spirometry is not known.
Detailed written questionnaires, full pulmonary function tests (including pre- and post-bronchodilator flow volume loops) and atopy testing were completed in 749 people recruited from a random population sample.
The GOLD-defined age-adjusted prevalence for adults ≥ 40 years old was 14.2% (95% CI, 11.0-17.0). This compared to a LLN-defined, age-adjusted, post-bronchodilator prevalence, in the same group of 9.0% (95% CI, 6.7 to 11.3).
The prevalence of COPD varied markedly depending on the definition used. Further research using longitudinal rather than cross-sectional data will help decide the preferred approach in COPD prevalence surveys.
PMCID: PMC2516341  PMID: 17666557
COPD; lower limit of normal; prevalence
23.  CT-based Biomarker Provides Unique Signature for Diagnosis of COPD Phenotypes and Disease Progression 
Nature medicine  2012;18(11):1711-1715.
Chronic obstructive pulmonary disease (COPD) is increasingly being recognized as a highly heterogeneous disorder, composed of varying pathobiology. Accurate detection of COPD subtypes by image biomarkers are urgently needed to enable individualized treatment thus improving patient outcome. We adapted the Parametric Response Map (PRM), a voxel-wise image analysis technique, for assessing COPD phenotype. We analyzed whole lung CT scans of 194 COPD individuals acquired at inspiration and expiration from the COPDGene Study. PRM identified the extent of functional small airways disease (fSAD) and emphysema as well as provided CT-based evidence that supports the concept that fSAD precedes emphysema with increasing COPD severity. PRM is a versatile imaging biomarker capable of diagnosing disease extent and phenotype, while providing detailed spatial information of disease distribution and location. PRMs ability to differentiate between specific COPD phenotypes will allow for more accurate diagnosis of individual patients complementing standard clinical techniques.
PMCID: PMC3493851  PMID: 23042237
24.  Lung matrix metalloproteinase-9 correlates with cigarette smoking and obstruction of airflow. 
Journal of Korean Medical Science  2003;18(6):821-827.
Cigarette smoking is the most important risk factor for obstruction of airflow in chronic obstructive pulmonary disease (COPD). Matrix metalloproteinases (MMPs) or an imbalance between MMPs and their inhibitors, the tissue inhibitors of MMP (TIMPs), is considered to play a role in the pathogenesis of COPD. We investigated whether the MMPs expression or the imbalance between MMPs and TIMP-1 is associated with the amount of cigarette smoking and the FEV1 value, in the lung parenchyma of 26 subjects (6 non-smokers and 20 cigarette smokers). First, we performed zymographic analysis to identify the profile of the MMPs, which revealed gelatinolytic bands mainly equivalent to MMP-9 in the smokers. We then measured, using enzyme immunoassay, the concentrations of MMP-9 and its inhibitor, TIMP-1. Correlation analysis revealed that both the MMP-9 concentrations and the molar ratios of MMP-9 to TIMP-1 (MMP-9/TIMP-1) were correlated with the amount of cigarette smoking. Furthermore, MMP-9 concentrations were inversely correlated with FEV1. In conclusion, this study shows that MMP-9 expression in human lung parenchyma is associated with cigarette smoking and also with the obstruction of airflow, suggesting that MMP-9 may play a role in the pathogenesis of the cigarette smoke-induced obstruction of airflow known as the characteristic of COPD.
PMCID: PMC3055149  PMID: 14676438
25.  Abrupt withdrawal of inhaled corticosteroids does not result in spirometric deterioration in chronic obstructive pulmonary disease: Effect of phenotyping? 
Annals of Thoracic Medicine  2012;7(4):238-242.
Some studies show a decline of FEV1 only one month after withdrawal of inhaled corticosteroids (ICS), while others show no decline. We speculate that the presence of an asthma phenotype in the Chronic Obstructive Pulmonary Disease (COPD) population, and that its exclusion may result in no spirometric deterioration.
We performed a prospective clinical observation study on 32 patients who fulfilled the Global Initiative for Chronic Obstructive lung disease definition of COPD (Grade II-IV). They were divided into two phenotypic groups. 1. Irreversible asthma (A and B) (n = 13): A. Asthma: Bronchial biopsy shows diffuse thickening of basement membrane (≥ 6.6 μm). B. Airflow limitation (AFL) likely to be asthma: KCO > 80% predicted if the patient refused biopsy. 2. COPD (A and B) (n = 19): A. COPD: hypercapneic respiratory failure with raised bicarbonate, panlobular emphysema with multiple bullas, or bronchial biopsy showing squamous metaplasia and epithelial/subepithelial inflammation without thickening of the basement membrane. B. AFL likely to be COPD: KCO < 80% predicted.
The asthma phenotype was significantly younger, had a strong association with hypertrophy of nasal turbinates, and registered a significant improvement of FEV1 (350 ml) vs a decline of - 26.5 ml in the COPD phenotype following therapy with budesonide/formoterol for one year. Withdrawal of budesonide for 4 weeks in the COPD phenotype resulted in FEV1 + 1.33% (SD ± 5.71) and FVC + 1.24% (SD ± 5.32); a change of <12% in all patients.
We recorded no spirometric deterioration after exclusion of the asthma phenotype from a COPD group.
PMCID: PMC3506105  PMID: 23189102
Asthma; COPD; radiology and other imaging; respiratory function tests

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