Rationale: A significant proportion of smokers have lung function impairment characterized by a reduced FEV1 with a preserved FEV1/FVC ratio. These smokers are a poorly characterized group due to their systematic exclusion from chronic obstructive pulmonary disease (COPD) studies.
Objectives: To characterize the clinical, functional, and radiographic features of Global Initiative for Chronic Obstructive Lung Disease (GOLD)-Unclassified (FEV1/FVC ≥ 0.7 and FEV1 < 80% predicted) and lower limits of normal (LLN)-unclassified (FEV1/FVC ≥ LLN and FEV1 < LLN) subjects compared to smokers with normal lung function and subjects with COPD.
Methods: Data from the first 2,500 subjects enrolled in the COPDGene study were analyzed. All subjects had 10 or more pack-years of smoking and were between the ages of 45 and 80 years. Multivariate regression models were constructed to determine the clinical and radiological variables associated with GOLD-Unclassified (GOLD-U) and LLN-Unclassified status. Separate multivariate regressions were performed in the subgroups of subjects with complete radiologic measurement variables available.
Measurements and Main Results: GOLD-U smokers account for 9% of smokers in COPDGene and have increased body mass index (BMI), a disproportionately reduced total lung capacity, and a higher proportion of nonwhite subjects and subjects with diabetes. GOLD-U subjects exhibit increased airway wall thickness compared to smoking control subjects and decreased gas trapping and bronchodilator responsiveness compared to subjects with COPD. When LLN criteria were used to define the “unclassified” group, African American subjects were no longer overrepresented. Both GOLD-U and LLN-Unclassified subjects demonstrated a wide range of lung function impairment, BMI, and percentage of total lung emphysema.
Conclusions: Subjects with reduced FEV1 and a preserved FEV1/FVC ratio are a heterogeneous group with significant symptoms and functional limitation who likely have a variety of underlying etiologies beyond increased BMI.
Clinical trial registered with www.clinicaltrials.gov (NCT000608764).
lung diseases, classification; lung diseases, diagnosis; lung diseases, epidemiology
Severe hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD). Long term oxygen therapy is beneficial in hypoxemic COPD patients. However, the clinical and radiographic predictors of hypoxemia and the use of oxygen therapy are not well described. This study aimed to find the correlates of resting hypoxemia and the pattern of oxygen use in moderate to severe COPD patients.
Subjects with GOLD stage II or higher COPD from the first 2500 COPDGene subjects were included in this analysis. All subjects were current or ex-smokers between ages 45 and 80. Severe resting hypoxemia was defined as room air oxygen saturation (SpO2) ≤ 88%. Use of supplemental oxygen therapy was determined by questionnaire.
Eighty-two of 1060 COPD subjects (7.7%) had severe resting hypoxemia. Twenty-one of the 82 (25.6%) were not using continuous supplemental oxygen. Female sex, higher BMI, lower FEV1, and enrollment in Denver were independent risk factors for hypoxemia; emphysema severity on quantitative chest CT scan did not predict hypoxemia. 132 of 971(13.6%) subjects without severe resting hypoxemia were using continuous supplemental oxygen. In non-hypoxemic oxygen users, Denver recruitment, higher BMI, lower FEV1, and more severe dyspnea were associated with the use of continuous oxygen.
A large number of COPD patients without severe hypoxemia were using supplemental oxygen therapy and the pattern of oxygen use was affected by factors other than resting SpO2 and emphysema severity. Longitudinal data will be required to reveal the effects of oxygen therapy in this subgroup.
Hypoxemia; long-term oxygen therapy; COPD; emphysema
Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV1 and FEV1/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.
Long-term therapy with systemic corticosteroids is not recommended in the treatment of chronic obstructive pulmonary disease (COPD). However, experience demonstrates that some patients receive low dose therapy. Our objective was to describe the demographic, physiologic and radiologic characteristics of COPD patients treated with chronic systemic corticosteroids. We analyzed COPD subjects with GOLD I–IV disease in the COPDGene® study. Subjects were divided into two groups based on whether they reported using chronic oral steroids or not. 1264 subjects were included. 58 (4.5%) reported chronic systemic corticosteroid use. There were no differences in age, race, comorbid conditions (other than asthma), or body mass index between the groups. There was a greater proportion of GOLD III (41% vs. 26%) and IV (41% vs. 13%) subjects in the group using chronic systemic corticosteroids. This group used more respiratory medications, required more oxygen (2.31±0.21 vs. 0.59±0.05 L/min; p<0.0001), and walked less distance (245.4±17.4 vs. 367.2±3.9 meters; p<0.0001). They reported more total (1.7±0.16 vs. 0.62±0.03; p<0.0001) and severe exacerbations per year (0.41±0.05 vs. 0.18 ± 0.01; p<0.0001). BODE (5.0±0.3 vs. 2.6±0.1; p<0.0001), MMRC (3.31±0.19 vs. 1.90±0.04; p<0.0001) and SGRQ scores (54.9±2.9 vs 53.3±0.6; p<0.0001) were higher. They also had a higher percentage of emphysema (22.4±1.9 vs. 14.0±0.4; %, p=<0.0001) on CT scan. COPD patients that report using chronic systemic corticosteroids have more severe clinical, physiologic, and radiographic disease.
Emphysema; Prednisone; Phenotype
COPDGeneis a multicenter observational study designed to identify genetic factors associated with COPD. It will also characterize chest CT phenotypes in COPD subjects, including assessment of emphysema, gas trapping, and airway wall thickening. Finally, subtypes of COPD based on these phenotypes will be used in a comprehensive genome-wide study to identify COPD susceptibility genes.
COPDGene will enroll 10,000 smokers with and without COPD across the GOLD stages. Both Non-Hispanic white and African-American subjects are included in the cohort. Inspiratory and expiratory chest CT scans will be obtained on all participants. In addition to the cross-sectional enrollment process, these subjects will be followed regularly for longitudinal studies. A genome-wide association study (GWAS) will be done on an initial group of 4000 subjects to identify genetic variants associated with case-control status and several quantitative phenotypes related to COPD. The initial findings will be verified in an additional 2000 COPD cases and 2000 smoking control subjects, and further validation association studies will be carried out.
COPDGene will provide important new information about genetic factors in COPD, and will characterize the disease process using high resolution CT scans. Understanding genetic factors and CT phenotypes that define COPD will potentially permit earlier diagnosis of this disease and may lead to the development of treatments to modify progression.
Rationale: Wood smoke–associated chronic obstructive pulmonary disease (COPD) is common in women in developing countries but has not been adequately described in developed countries.
Objectives: Our objective was to determine whether wood smoke exposure was a risk factor for COPD in a population of smokers in the United States and whether aberrant gene promoter methylation in sputum may modify this association.
Methods: For this cross-sectional study, 1,827 subjects were drawn from the Lovelace Smokers' Cohort, a predominantly female cohort of smokers. Wood smoke exposure was self-reported. Postbronchodilator spirometry was obtained, and COPD outcomes studied included percent predicted FEV1, airflow obstruction, and chronic bronchitis. Effect modification of wood smoke exposure with current cigarette smoke, ethnicity, sex, and promoter methylation of lung cancer-related genes in sputum on COPD outcomes were separately explored. Multivariable logistic and poisson regression models were used for binary and rate-based outcomes, respectively.
Measurements and Main Results: Self-reported wood smoke exposure was independently associated with a lower percent predicted FEV1 (point estimate [± SE] −0.03 ± 0.01) and a higher prevalence of airflow obstruction and chronic bronchitis (odds ratio, 1.96; 95% confidence interval, 1.52–2.52 and 1.64 (95% confidence interval, 1.31–2.06, respectively). These associations were stronger among current cigarette smokers, non-Hispanic whites, and men. Wood smoke exposure interacted in a multiplicative manner with aberrant promoter methylation of the p16 or GATA4 genes on lower percent predicted FEV1.
Conclusions: These studies identify a novel link between wood smoke exposure and gene promoter methylation that synergistically increases the risk for reduced lung function in cigarette smokers.
wood smoke; cigarette smokers; airflow obstruction; gene promoter methylation in sputum DNA
The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10−9). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV1 (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.
Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality in blacks. The prevalence of COPD among blacks was estimated from the spirometry data obtained from the first National Health and Nutrition Examination Survey (NHANES), 1971-1975. Of 873 subjects, 585 (67%) had acceptable spirometry trials. Chronic obstructive pulmonary disease was defined as a forced expiratory volume in one second (FEV1) less than 65% of the predicted value. The mean FEV1 percentage predicted was 96.7%. The overall prevalence of COPD was 5.4%; 3.7% for males and 6.7% for females. The prevalence was significantly higher with age for both males and females. The multiple logistic regression analyses showed that age and sex were associated with COPD but respiratory symptoms did not attain statistical significance.
The value of quantitative computed tomography (QCT) to identify chronic obstructive pulmonary disease (COPD) phenotypes is increasingly appreciated. We hypothesized that QCT-defined emphysema and airway abnormalities relate to St. George's Respiratory Questionnaire (SGRQ) and BODE.
1,200 COPDGene subjects meeting GOLD criteria for COPD with QCT analysis were included. Total lung emphysema was measured using density mask technique with a -950 HU threshold. An automated program measured mean wall thickness (WT), wall area percent (WA%) and pi10 in six segmental bronchi. Separate multivariate analyses examined the relative influence of airway measures and emphysema on SGRQ and BODE.
In separate models predicting SGRQ score, a one unit standard deviation (SD) increase in each airway measure predicted higher SGRQ scores (for WT, 1.90 points higher, p=0.002; for WA%, 1.52 points higher, p=0.02; for pi10, 2.83 points higher p<0.001). The comparable increase in SGRQ for a one unit SD increase in percent emphysema in these models was relatively weaker, significant only in the pi10 model (for percent emphysema, 1.45 points higher, p=0.01). In separate models predicting BODE, a one unit SD increase in each airway measure predicted higher BODE scores (for WT, 1.07 fold increase, p<0.001; for WA%, 1.20 fold increase, p<0.001; for pi10, 1.16 fold increase, p<0.001). In these models, emphysema more strongly influenced BODE (range 1.24-1.26 fold increase, p<0.001).
Emphysema and airway disease both relate to clinically important parameters. The relative influence of airway disease is greater for SGRQ; the relative influence of emphysema is greater for BODE.
Imaging; COPD; emphysema
Alpha-1-antitrypsin deficiency is a genetic condition associated with severe, early-onset chronic obstructive pulmonary disease (COPD). However, there is significant variability in lung function impairment among persons with the protease inhibitor ZZ genotype. Early identification of persons at highest risk of developing lung disease could be beneficial in guiding monitoring and treatment decisions. Using a multicenter, family-based study sample (2002–2005) of 372 persons with the protease inhibitor ZZ genotype, the authors developed prediction models for forced expiratory volume in 1 second (FEV1) and the presence of severe COPD using demographic, clinical, and genetic variables. Half of the data sample was used for model development, and the other half was used for model validation. In the training sample, variables found to be predictive of both FEV1 and severe COPD were age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status. In the validation sample, the predictive model for FEV1 explained 50% of the variance in FEV1, and the model for severe COPD exhibited excellent discrimination (c statistic = 0.88).
alpha-1-antitrypsin deficiency; genetics; polymorphism, single nucleotide; pulmonary disease, chronic obstructive
Rationale: The epidemiology of cigarette smoking–related chronic obstructive pulmonary disease (COPD) is not well characterized in Hispanics in the United States. Understanding how ethnicity influences COPD is important for a number of reasons, from informing public health policies to dissecting the genetic and environmental effects that contribute to disease.
Objectives: The present study assessed differences in risk between Hispanics and non-Hispanic whites for longitudinal and cross-sectional COPD phenotypes. Genetic ancestry was used to verify findings based on self-reported ethnicity. Hispanics in New Mexico are primarily differentiated from non-Hispanic whites by their proportion of Native American ancestry.
Methods: The study was performed in a New Mexican cohort of current and former smokers. Self-reported Hispanic and non-Hispanic white ethnicity was validated by defining genetic ancestry proportions at the individual level using 48 single-nucleotide polymorphism markers. Self-reported ethnicity and genetic ancestry were independently used to assess associations with cross-sectional and longitudinal measures of lung function. Multivariable models were adjusted for indicators of smoking behavior.
Measurements and Main Results: Self-reported Hispanic ethnicity was significantly associated with lower odds of COPD (odds ratio, 0.49; 95% confidence interval, 0.35–0.71; P = 0.007), and this protection was validated by the observation that Hispanic smokers have reduced risk of rapid decline in lung function (odds ratio, 0.48; 95% confidence interval, 0.30–0.78; P = 0.003). Similar findings were noted when Native American genetic ancestry proportions were used as predictors instead of self-report of Hispanic ethnicity.
Conclusions: Hispanic ethnicity is inversely associated with cross-sectional and longitudinal spirometric COPD phenotypes even after adjustment for smoking. Native American genetic ancestry may account for this “Hispanic protection.”
Rationale: Several occupational exposures adversely affect lung function.
Objectives: This study reports the influence of continued occupational dust and fume exposures on the rate of decline of lung function in participants with early chronic obstructive pulmonary disease (COPD) studied in a population-based study.
Methods: Subjects consisted of 5,724 participants in the Lung Health Study, a multicenter study of smoking cessation and anticholinergic bronchodilator administration in smokers with early COPD (3,592 men; 2,132 women). Average post-bronchodilator FEV1 at entry was 78.4% predicted for men and 78.2% predicted for women; all participants had an FEV1/FVC ratio less than 0.70.
Measurements and Main Results: Participants underwent a baseline evaluation and five annual follow-up assessments, including questionnaires and spirometry. The effect of ongoing dust or fume exposure on FEV1 in each follow-up year was statistically evaluated with a mixed-effects regression model, which was adjusted for FEV1 at entry, age, airway responsiveness to methacholine, baseline smoking intensity, and time-varying (yearly) smoking status during each follow-up year. In men with early COPD, each year of continued fume exposure was associated with a 0.25% predicted reduction in post-bronchodilator FEV1% predicted. Continued smoking and airway hyperresponsiveness were also associated with reduction in FEV1 during each year of follow-up in both men and women. Statistically significant effects of dust exposure on the rate of decline were not found, nor were effects of fume exposure noted in women.
Conclusions: These results suggest a need for secondary prevention by controlling occupational fume exposures.
forced expiratory volume; longitudinal studies; pulmonary disease, chronic obstructive
Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups.
We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV1]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV1 and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD.
The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [−82A→G]) was positively associated with FEV1 in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2×10−6). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P = 0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P = 0.005) and among participants in a family-based study of early-onset COPD (P = 0.006).
The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers.
Chronic obstructive pulmonary disease (COPD) is characterized by alveolar destruction and abnormal inflammatory responses to noxious stimuli. Surfactant protein–D (SFTPD) is immunomodulatory and essential to host defense. We hypothesized that polymorphisms in SFTPD could influence the susceptibility to COPD. We genotyped six single-nucleotide polymorphisms (SNPs) in surfactant protein D in 389 patients with COPD in the National Emphysema Treatment Trial (NETT) and 472 smoking control subjects from the Normative Aging Study (NAS). Case-control association analysis was performed using Cochran–Armitage trend tests and multivariate logistic regression. The replication of significant associations was attempted in the Boston Early-Onset COPD Study, the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and the Bergen Cohort. We also correlated SFTPD genotypes with serum concentrations of surfactant protein–D (SP-D) in the ECLIPSE Study. In the NETT–NAS case-control analysis, four SFTPD SNPs were associated with susceptibility to COPD: rs2245121 (P = 0.01), rs911887 (P = 0.006), rs6413520 (P = 0.004), and rs721917 (P = 0.006). In the family-based analysis of the Boston Early-Onset COPD Study, rs911887 was associated with prebronchodilator and postbronchodilator FEV1 (P = 0.003 and P = 0.02, respectively). An intronic SNP in SFTPD, rs7078012, was associated with COPD in the ECLIPSE Study and the Bergen Cohort. Multiple SFTPD SNPs were associated with serum SP-D concentrations in the ECLIPSE Study. We demonstrated an association of polymorphisms in SFTPD with COPD in multiple populations. We demonstrated a correlation between SFTPD SNPs and SP-D protein concentrations. The SNPs associated with COPD and SP-D concentrations differed, suggesting distinct genetic influences on susceptibility to COPD and SP-D concentrations.
COPD; surfactant protein–D; single-nucleotide polymorphisms; genetics
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.
chronic obstructive pulmonary disease; spirometry; respiratory function tests
Chronic obstructive pulmonary diseases (COPD) have been defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as irreversible conditions which are diagnosed by fixed cut-off points of FEV1/FVC.
The aim of this study was to determine the cut-off points for FEV1/FEV6 ratio and FEV6 as alternatives for FEV1/FVC and FVC in detection of airway obstruction and lung restriction, respectively.
Materials and Methods
A total of 318 Spiro metric examinations of subjects referred to Shariati hospital were analyzed. A subject was considered to have obstruction if FEV1/FVC was lower than 70%. The restriction was defined as FVC < 80% in the absence of obstruction. The Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of FEV1/FEV6 and FEV6 were calculated.
This study shows that the current cut-off points used to detect obstruction and restriction can be replaced by FEV1/FEV6 < 71% and FEV6 < 83%, respectively. FEV1/FEV6 had sensitivity of 95.5% and specificity of 99.4%; the PPV and NPVs were 99.3% and 96.3%. The prevalence of obstruction was 49.4%. For restrictive pattern, FEV6 had sensitivity of 93%, specificity of 79.5% with PPV of 18% and NPV of 99.5%. The prevalence of restriction was 6.3%.
The FEV1/FEV6 ratio can be used as a valid surrogate for FEV1/FVC in the diagnosis of airway obstruction, especially for screening purposes in high-risk populations for COPD. Moreover, FEV6 is an acceptable alternative for FVC in detection of restrictive pattern.
Pulmonary Disease, Chronic Obstructive; Pulmonary Function Tests
Rationale: Patients with severe chronic obstructive pulmonary disease (COPD) may have varying levels of disability despite similar levels of lung function. This variation may reflect different COPD subtypes, which may have different genetic predispositions.
Objectives: To identify genetic associations for COPD-related phenotypes, including measures of exercise capacity, pulmonary function, and respiratory symptoms.
Methods: In 304 subjects from the National Emphysema Treatment Trial, we genotyped 80 markers in 22 positional and/or biologically plausible candidate genes. Regression models were used to test for association, using a test–replication approach to guard against false-positive results. For significant associations, effect estimates were recalculated using the entire cohort. Positive associations with dyspnea were confirmed in families from the Boston Early-Onset COPD Study.
Results: The test–replication approach identified four genes—microsomal epoxide hydrolase (EPHX1), latent transforming growth factor-β binding protein-4 (LTBP4), surfactant protein B (SFTPB), and transforming growth factor-β1 (TGFB1)—that were associated with COPD-related phenotypes. In all subjects, single-nucleotide polymorphisms (SNPs) in EPHX1 (p ⩽ 0.03) and in LTBP4 (p ⩽ 0.03) were associated with maximal output on cardiopulmonary exercise testing. Markers in LTBP4 (p ⩽ 0.05) and SFTPB (p = 0.005) were associated with 6-min walk test distance. SNPs in EPHX1 were associated with carbon monoxide diffusing capacity (p ⩽ 0.04). Three SNPs in TGFB1 were associated with dyspnea (p ⩽ 0.002), one of which replicated in the family study (p = 0.02).
Conclusions: Polymorphisms in several genes seem to be associated with COPD-related traits other than FEV1. These associations may identify genes in pathways important for COPD pathogenesis.
dyspnea; emphysema; exercise tolerance; genetic association; pulmonary function tests
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for chronic obstructive pulmonary disease (COPD) uses the post-bronchodilator spirometry for diagnosis and severity staging. We evaluated differences in the severity classification of COPD, based on pre- and post-bronchodilator spirometry.
Materials and Methods
From 2000 to 2004, 207 COPD patients who underwent spirometry before and after inhalation of 400 µg of fenoterol were analyzed. A responder to the bronchodilator test (BDT) was defined by the American Thoracic Society (ATS) as an increase in forced expiratory volume in one second (FEV1) or forced vital capacity ≥ 12% and ≥ 200 mL, and by the European Respiratory Society (ERS) as an increase in FEV1 ≥ 10% of the predicted value. COPD severity was classified according to the 2008 GOLD guidelines.
For the entire study population, the FEV1 increased by 11.8 ± 12.5% of baseline after BDT and 41.1% and 27.1% of subjects were classified as responders using the ATS and ERS criteria, respectively. Based on pre-BDT spirometry, 55, 85, 58, and 9 patients were classified as Stage I-IV COPD, respectively. Sixty-seven (32.4%) patients changed severity staging after BDT, including 20.0%, 28.2%, 44.8%, and 66.7% of pre-BDT patients Stages I through IV, respectively. More ATS or ERS BDT-responders had a change in severity staging than non-responders (52.9% vs. 18.9% and 62.5% vs. 21.2%, both p < 0.001).
Our data suggest that the severity staging of COPD using pre-BDT spirometry might lead to significant differences as compared to staging, based on post-BDT spirometry, as recommended by the current GOLD guidelines.
Bronchodilator test; chronic obstructive pulmonary disease; severity staging
Rationale: Genomic loci are associated with FEV1 or the ratio of FEV1 to FVC in population samples, but their association with chronic obstructive pulmonary disease (COPD) has not yet been proven, nor have their combined effects on lung function and COPD been studied.
Objectives: To test association with COPD of variants at five loci (TNS1, GSTCD, HTR4, AGER, and THSD4) and to evaluate joint effects on lung function and COPD of these single-nucleotide polymorphisms (SNPs), and variants at the previously reported locus near HHIP.
Methods: By sampling from 12 population-based studies (n = 31,422), we obtained genotype data on 3,284 COPD case subjects and 17,538 control subjects for sentinel SNPs in TNS1, GSTCD, HTR4, AGER, and THSD4. In 24,648 individuals (including 2,890 COPD case subjects and 13,862 control subjects), we additionally obtained genotypes for rs12504628 near HHIP. Each allele associated with lung function decline at these six SNPs contributed to a risk score. We studied the association of the risk score to lung function and COPD.
Measurements and Main Results: Association with COPD was significant for three loci (TNS1, GSTCD, and HTR4) and the previously reported HHIP locus, and suggestive and directionally consistent for AGER and TSHD4. Compared with the baseline group (7 risk alleles), carrying 10–12 risk alleles was associated with a reduction in FEV1 (β = –72.21 ml, P = 3.90 × 10−4) and FEV1/FVC (β = –1.53%, P = 6.35 × 10−6), and with COPD (odds ratio = 1.63, P = 1.46 × 10−5).
Conclusions: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.
FEV1; FVC; genome-wide association study; modeling risk
The destruction of elastic fibers has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Emphysema has been described in autosomal dominant cutis laxa, which can be caused by mutations in the elastin gene. Previously, a rare functional mutation in the terminal exon of elastin was found in a case of severe, early-onset COPD. To test the hypothesis that other similar elastin mutations may predispose to COPD, we screened 90 probands from the Boston Early-Onset COPD Study and 90 smoking control subjects from the Normative Aging Study for mutations in elastin exons using high-resolution DNA melt analysis followed by resequencing. Rare nonsynonymous single-nucleotide polymorphisms (SNPs) seen only in cases were examined for segregation with airflow obstruction within pedigrees. Common nonsynonymous SNPs were tested for association with COPD in a family-based analysis of 949 subjects from the Boston Early-Onset COPD Study, and in a case–control analysis in 389 COPD cases from the National Emphysema Treatment Trial and 472 control subjects from the Normative Aging Study. Of 28 elastin variants found, 3 were nonsynonymous SNPs found only in cases. The previously described Gly773Asp mutation was found in another proband. The other two SNPs did not clearly segregate with COPD within families. Two common nonsynonymous SNPs did not demonstrate significant associations in either a family-based or case–control analysis. Exonic SNPs in the elastin gene do not appear to be common risk factors for severe COPD.
elastin; chronic obstructive pulmonary disease; emphysema; genetic polymorphism
Background: A study was undertaken to define the risk of death among a national cohort of US adults both with and without lung disease.
Methods: Participants in the first National Health and Nutrition Examination Survey (NHANES I) followed for up to 22 years were studied. Subjects were classified using a modification of the Global Initiative for Chronic Obstructive Lung Disease criteria for chronic obstructive pulmonary disease (COPD) into the following mutually exclusive categories using the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and the presence of respiratory symptoms: severe COPD, moderate COPD, mild COPD, respiratory symptoms only, restrictive lung disease, and no lung disease. Proportional hazard models were developed that controlled for age, race, sex, education, smoking status, pack years of smoking, years since quitting smoking, and body mass index.
Results: A total of 1301 deaths occurred in the 5542 adults in the cohort. In the adjusted proportional hazards model the presence of severe or moderate COPD was associated with a higher risk of death (hazard ratios (HR) 2.7 and 1.6, 95% confidence intervals (CI) 2.1 to 3.5 and 1.4 to 2.0), as was restrictive lung disease (HR 1.7, 95% CI 1.4 to 2.0).
Conclusions: The presence of both obstructive and restrictive lung disease is a significant predictor of earlier death in long term follow up.
To determine the feasibility of using an accelerometer to characterize physical activity patterns (PA) surrounding chronic obstructive pulmonary disease (COPD) exacerbations (AECOPD) in patients with COPD for 16 weeks.
Patients with COPD (n = 8) wore the RT3®, a triaxial accelerometer (Stayhealthy, Monrovia, CA) during waking hours and kept daily symptom diaries. The mean vector magnitude unit (VMU) per minute was calculated by dividing the total VMU for the day by the number of minutes the device was worn. Descriptive statistics were used and plots were made showing PA for each subject with AECOPD markers based on symptom diaries and health resource utilization.
Sample characteristics were: age 71 ± 4; 5 Females; forced expiratory volume in one second (FEV1)% predicted: 40% ± 16%; FEV1/forced vital capacity: 45 ± 7; and Medical Research Council dyspnea scale: 2.3 ± 0.9. Overall adherence to the monitoring protocol was 97.6% (Range 92%–100%) while adherence to wearing the device for at least 10 hours per day was 91.5% (Range 75%–99%). Mean vector magnitude units per minute was 117.8 ± 47 (Range 61.4–184.1). Seven exacerbations were captured over a total of 896 person-days of monitoring. There were substantial intra-individual fluctuations in daily PA during both the stable state and with outpatient treated exacerbations.
Patients with COPD were able to adhere to a 16-week activity monitoring protocol and reported a willingness to wear such a device for an extended period of time if the data yield important and useful information for themselves and their health provider. Future work will need to focus first, on validating other promising devices that produce higher quality PA data and second, replicate this monitoring protocol with a larger sample of COPD patients over a longer period.
physical activity; accelerometry; COPD; exacerbations
Rationale: Hypercapnic respiratory failure because of inspiratory muscle weakness is the most important cause of death in chronic obstructive pulmonary disease (COPD). However, the pathophysiology of failure of the diaphragm to generate force in COPD is in part unclear. Objectives: The present study investigated contractile function and myosin heavy chain content of diaphragm muscle single fibers from patients with COPD. Methods: Skinned muscle fibers were isolated from muscle biopsies from the diaphragm of eight patients with mild to moderate COPD and five patients without COPD (mean FEV1 % predicted, 70 and 100%, respectively). Contractile function of single fibers was assessed, and afterwards, myosin heavy chain content was determined in these fibers. In diaphragm muscle homogenates, the level of ubiquitin-protein conjugation was determined. Results: Diaphragm muscle fibers from patients with COPD showed reduced force generation per cross-sectional area, and reduced myosin heavy chain content per half sarcomere. In addition, these fibers had decreased Ca2+ sensitivity of force generation, and slower cross-bridge cycling kinetics. Our observations were present in fibers expressing slow and 2A isoforms of myosin heavy chain. Ubiquitin-protein conjugation was increased in diaphragm muscle homogenates of patients with mild to moderate COPD. Conclusions: Early in the development of COPD, diaphragm fiber contractile function is impaired. Our data suggest that enhanced diaphragm protein degradation through the ubiquitin-proteasome pathway plays a role in loss of contractile protein and, consequently, failure of the diaphragm to generate force.
contractility; myosin; single fiber; ubiquitin
Rationale: Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified.
Objectives: We used high-density single-nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD.
Methods: On chromosome 12p, we genotyped 1,387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial and 424 control smokers from the Normative Aging Study. SNPs with significant associations were then tested in the BEOCOPD study and the International COPD Genetics Network. Based on the human results, we assessed histology and gene expression in the lungs of Sox5−/− mice.
Measurements and Main Results: In the case-control analysis, 27 SNPs were significant at P ≤ 0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (National Emphysema Treatment Trial–Normative Aging Study P = 6.0 × 10−4, BEOCOPD P = 1.5 × 10−5, combined P = 1.7 × 10−7), located 3′ to the gene SOX5. Association with rs11046966 was not replicated in the International COPD Genetics Network. Sox5−/− mice showed abnormal lung development, with a delay in maturation before the saccular stage, as early as E16.5. Lung pathology in Sox5−/− lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis.
Conclusions: Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.
chronic obstructive pulmonary disease; emphysema; knockout mice; lung development; single nucleotide polymorphism
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.