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1.  Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease 
Rationale: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility.
Objectives: To identify coding variants associated with COPD.
Methods: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts.
Measurements and Main Results: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10−14) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10−6) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10−8) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM.
Conclusions: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.
PMCID: PMC4960630  PMID: 26771213
chronic obstructive pulmonary disease; genetics; exome; IL-27
2.  Early efficacy of budesonide/formoterol in patients with moderate-to-very-severe COPD 
Background and objective
Large clinical trials have confirmed the long-term efficacy of inhaled corticosteroid/long-acting β2-agonist combinations in patients with chronic obstructive pulmonary disease (COPD). It was hypothesized that significant treatment effects would already be present within 3 months after the initiation of treatment across a range of clinical outcomes, irrespective of COPD severity.
Post hoc analysis of 3-month post-randomization outcomes, including exacerbation rates, dropouts, symptoms, reliever use, and lung function, from three studies with similar inclusion criteria of moderate-to-very-severe COPD. Patients (n=1,571) were treated with budesonide/formoterol (B/F) 320/9 μg or placebo, twice daily; in one study, tiotropium 18 μg once daily was also given.
Over the first 3 months of treatment, fewer patients randomized to B/F experienced exacerbations versus the placebo group (111 and 196 patients with ≥1 exacerbation, respectively). This was true in each COPD severity group. Compared with placebo, B/F treatment led to significantly lower 3-month exacerbation rates in the moderate and severe COPD severity groups (46% and 57% reduction, respectively), with a nonsignificant reduction (29%) in very severe COPD. Fewer dropouts occurred among patients treated with B/F versus placebo, this effect being greater with increasing COPD severity. B/F was associated with improved forced expiratory volume in 1 s, morning peak expiratory flow rate, total reliever use, and total symptom score versus placebo.
Treatment with B/F decreased exacerbations in patients with moderate-to-very-severe COPD within 3 months of commencing treatment. This effect was paralleled by improved lung function, less reliever medication use, and fewer symptoms, irrespective of disease severity.
PMCID: PMC5182036  PMID: 28031707
bronchodilator agents; clinical respiratory medicine; clinical trials; COPD
3.  Clinical, physiologic, and radiographic factors contributing to development of hypoxemia in moderate to severe COPD: a cohort study 
BMC Pulmonary Medicine  2016;16:169.
Hypoxemia is a major complication of COPD and is a strong predictor of mortality. We previously identified independent risk factors for the presence of resting hypoxemia in the COPDGene cohort. However, little is known about characteristics that predict onset of resting hypoxemia in patients who are normoxic at baseline. We hypothesized that a combination of clinical, physiologic, and radiographic characteristics would predict development of resting hypoxemia after 5-years of follow-up in participants with moderate to severe COPD
We analyzed 678 participants with moderate-to-severe COPD recruited into the COPDGene cohort who completed baseline and 5-year follow-up visits and who were normoxic by pulse oximetry at baseline. Development of resting hypoxemia was defined as an oxygen saturation ≤88% on ambient air at rest during follow-up. Demographic and clinical characteristics, lung function, and radiographic indices were analyzed with logistic regression models to identify predictors of the development of hypoxemia.
Forty-six participants (7%) developed resting hypoxemia at follow-up. Enrollment at Denver (OR 8.30, 95%CI 3.05–22.6), lower baseline oxygen saturation (OR 0.70, 95%CI 0.58–0.85), self-reported heart failure (OR 6.92, 95%CI 1.56–30.6), pulmonary artery (PA) enlargement on computed tomography (OR 2.81, 95%CI 1.17–6.74), and prior severe COPD exacerbation (OR 3.31, 95%CI 1.38–7.90) were independently associated with development of resting hypoxemia. Participants who developed hypoxemia had greater decline in 6-min walk distance and greater 5-year decline in quality of life compared to those who remained normoxic at follow-up.
Development of clinically significant hypoxemia over a 5-year span is associated with comorbid heart failure, PA enlargement and severe COPD exacerbation. Further studies are needed to determine if treatments targeting these factors can prevent new onset hypoxemia.
Trial registration
COPDGene is registered at NCT00608764 (Registration Date: January 28, 2008)
Electronic supplementary material
The online version of this article (doi:10.1186/s12890-016-0331-0) contains supplementary material, which is available to authorized users.
PMCID: PMC5131397  PMID: 27903260
4.  Right Ventricular Diastolic Function and Exercise Capacity in COPD 
Respiratory medicine  2015;109(10):1287-1292.
Decreased exercise capacity in chronic obstructive pulmonary disease (COPD) is incompletely explained by pulmonary pathologic and physiologic abnormalities. We evaluated the extent to which right ventricular diastolic function (RVDF) is associated with exercise capacity in COPD.
Fifty-one patients with COPD were evaluated by echocardiography, spirometry, and the 6 minute walk test (6MWT). RVDF was assessed using 4 echocardiographic parameters: 1) the ratio of tricuspid valve (TV) early (E) and late (A) inflow velocities (TV E/A) 2) TV early tissue Doppler velocity (TV e’) 3) TV deceleration time (DT) and 4) the ratio of TV E and e’ velocities (TV E/e’). Multiple linear regression was used to examine the extent to which these parameters were associated with 6MWT distance. All models adjusted for age, sex, post-bronchodilator FEV1/FVC, resting heart rate, and use of supplemental O2 during 6MWT. A regression model was calculated for each of the 4 markers of RVDF.
Forty-seven percent of the sample had GOLD stage III or IV COPD. All 51 subjects had preserved left ventricular ejection fraction (LVEF, mean = 71.7%, SD = 7.8%). A higher TV E/A ratio was associated with increased 6MWT distance (p = 0.001). TV e’, TV DT and TV E/e’ did not have a statistically significant association with 6MWT distance in regression models.
In a cohort with moderate to severe COPD and normal LVEF, TV E/A was associated with 6MWT distance after adjusting for relevant demographic and medical covariates. RV diastolic dysfunction may independently contribute to exercise intolerance in COPD.
PMCID: PMC4745988  PMID: 26371994
COPD; right ventricle; exercise; diastolic function
5.  Genome-wide site-specific differential methylation in the blood of individuals with Klinefelter Syndrome 
Klinefelter syndrome (KS) (47 XXY) is a common sex-chromosome aneuploidy with an estimated prevalence of 1 in every 660 male births. Investigations into the associations between DNA methylation and the highly variable clinical manifestations of KS have largely focused on the supernumerary X chromosome; systematic investigations of the epigenome have been limited. We obtained genome-wide DNA methylation data from peripheral blood using the Illumina HumanMethylation450K platform in 5 KS (47 XXY), 102 male (46 XY), and 113 female (46 XX) control subjects participating in the chronic obstructive pulmonary disease (COPD) Gene Study. Empirical Bayes-mediated models were used to test for differential methylation by KS status. CpG sites with a false-discovery rate <0.05 from the first-generation HumanMethylation27K platform were further examined in an independent replication cohort of 2 KS subjects, 590 male, and 495 female controls drawn from the International COPD Genetics Network (ICGN). Differential methylation at sites throughout the genome were identified, including 86 CpG sites that were differentially methylated in KS subjects relative to both male and female controls. CpG sites annotated to the HEN1 methyltransferase homolog 1 (HENMT1), calcyclin-binding protein (CACYBP), and GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1) genes were among the “KS-specific” loci that were replicated in ICGN. We therefore conclude that site-specific differential methylation exists throughout the genome in KS. The functional impact and clinical relevance of these differentially methylated loci should be explored in future studies.
PMCID: PMC4439255  PMID: 25988574
[MeSH]: Klinefelter syndrome; DNA methylation; epigenomics; XXY syndrome
6.  A Genome-wide analysis of the response to inhaled beta2-agonists in Chronic Obstructive Pulmonary Disease 
The pharmacogenomics journal  2015;16(4):326-335.
Short-acting β2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified.
We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African American and four white populations. BDR was defined as the quantitative spirometric response to inhaled β2-agonists. We combined results in a meta-analysis.
In the meta-analysis, SNPs in the genes KCNK1 (P=2.02×10−7) and KCNJ2 (P=1.79×10−7) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1×10−9). A nominal association with CDH13 was identified in a gene-based analysis in all subjects.
We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.
PMCID: PMC4848212  PMID: 26503814
7.  Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia 
BMC Genetics  2016;17:74.
Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci.
We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 Pmeta = 3.7 × 10−09). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10−7 and DQB1*06:02 P = 6.1 × 10−8). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10−16).
We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-016-0377-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4895966  PMID: 27266705
Pulmonary fibrosis; HLA association; Imputation; Gene expression; RNA-Seq
8.  Reduced Bone Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk 
Rationale: Former smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered.
Objectives: To demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women.
Methods: Characteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use.
Measurements and Main Results: vBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58% of all subjects, was more frequent in those with worse COPD, and rose to 84% among subjects with very severe COPD. Vertebral fractures were present in 37% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures.
Conclusions: Male smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.
PMCID: PMC4418341  PMID: 25719895
low bone density; COPD; vertebral fractures; quantitative computed tomography; smoking
9.  Clinical and Radiologic Disease in Smokers With Normal Spirometry 
JAMA internal medicine  2015;175(9):1539-1549.
Airflow obstruction on spirometry is universally used to define chronic obstructive pulmonary disease (COPD), and current or former smokers without airflow obstruction may assume that they are disease free.
To identify clinical and radiologic evidence of smoking-related disease in a cohort of current and former smokers who did not meet spirometric criteria for COPD, for whom we adopted the discarded label of Global Initiative for Obstructive Lung Disease (GOLD) 0.
Individuals from the Genetic Epidemiology of COPD (COPDGene) cross-sectional observational study completed spirometry, chest computed tomography (CT) scans, a 6-minute walk, and questionnaires. Participants were recruited from local communities at 21 sites across the United States. The GOLD 0 group (n = 4388) (ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity >0.7 and FEV1 ≥80% predicted) from the COPDGene study was compared with a GOLD 1 group (n = 794), COPD groups (n = 3690), and a group of never smokers (n = 108). Recruitment began in January 2008 and ended in July 2011.
Physical function impairments, respiratory symptoms, CT abnormalities, use of respiratory medications, and reduced respiratory-specific quality of life.
One or more respiratory-related impairments were found in 54.1% (2375 of 4388) of the GOLD 0 group. The GOLD 0 group had worse quality of life (mean [SD] St George’s Respiratory Questionnaire total score, 17.0 [18.0] vs 3.8 [6.8] for the never smokers; P < .001) and a lower 6-minute walk distance, and 42.3% (127 of 300) of the GOLD 0 group had CT evidence of emphysema or airway thickening. The FEV1 percent predicted distribution and mean for the GOLD 0 group were lower but still within the normal range for the population. Current smoking was associated with more respiratory symptoms, but former smokers had greater emphysema and gas trapping. Advancing age was associated with smoking cessation and with more CT findings of disease. Individuals with respiratory impairments were more likely to use respiratory medications, and the use of these medications was associated with worse disease.
Lung disease and impairments were common in smokers without spirometric COPD. Based on these results, we project that there are 35 million current and former smokers older than 55 years in the United States who may have unrecognized disease or impairment. The effect of chronic smoking on the lungs and the individual is substantially underestimated when using spirometry alone.
PMCID: PMC4564354  PMID: 26098755
10.  Comparison between an Alternative and the Classic Definition of Chronic Bronchitis in COPDGene 
Rationale: Previous studies on chronic bronchitis (CB) have used varying definitions.
Objectives: We sought to compare an alternative CB definition, using the St. George’s Respiratory Questionnaire (SGRQ), a commonly used assessment tool, with the classic definition and to investigate if it had independent or additive value.
Methods: We analyzed data from 4,513 subjects from Global Initiative for Chronic Obstructive Lung Disease groups 1 to 4 in the COPDGene cohort. We compared the classic definition of CB with the SGRQ definition, defined by their answers to the questions about both cough and phlegm. We compared the Classic CB+ versus CB− groups, and the SGRQ CB+ and CB− groups. We also analyzed the cohort split into four groups: Classic CB+/SGRQ CB+, Classic CB+/SGRQ CB−, Classic CB−/SGRQ CB+, Classic CB−/SGRQ CB−.
Measurements and Main Results: A total of 26.1% subjects were Classic CB+, whereas 39.9% were SGRQ CB+. When the SGRQ definition was compared with the Classic CB definition, using this as the gold standard, the SGRQ CB definition had a sensitivity and specificity of 0.87 and 0.77, respectively. The SGRQ CB+ and Classic CB+ groups were strikingly similar, with more respiratory symptoms and exacerbations, worse lung function, and greater airway wall thickness. In addition, the Classic CB+/SGRQ CB+, Classic CB+/SGRQ CB−, and Classic CB−/SGRQ CB+ groups shared similar characteristics as well.
Conclusions: The SGRQ CB definition identifies more subjects with chronic cough and sputum who share a similar phenotype identified by the Classic CB definition. The addition of the SGRQ CB definition to the classic one can be used to identify more patients with chronic obstructive pulmonary disease at risk for poor outcomes.
PMCID: PMC4418311  PMID: 25575351
chronic obstructive pulmonary disease; chronic bronchitis; Saint George’s Respiratory Questionnaire
11.  Early response to inhaled bronchodilators and corticosteroids as a predictor of 12-month treatment responder status and COPD exacerbations 
Early treatment response markers, for example, improvement in forced expiratory volume in 1 second (FEV1) and St George’s Respiratory Questionnaire (SGRQ) total score, may help clinicians to better manage patients with chronic obstructive pulmonary disease (COPD). We investigated the prevalence of clinically important improvements in FEV1 and SGRQ scores after 2-month budesonide/formoterol or formoterol treatment and whether such improvements predict subsequent improvements and exacerbation rates.
This post hoc analysis is based on data from three double-blind, randomized studies in patients with moderate-to-very-severe COPD receiving twice-daily budesonide/formoterol or formoterol alone for 6 or 12 months. Prebronchodilator FEV1 and SGRQ total score were measured before treatment and at 2 and 12 months; COPD exacerbation rates were measured during months 2–12. Responders were defined by ≥100 mL improvement in prebronchodilator FEV1 and ≥4-point decrease in SGRQ total score.
Overall, 2,331 and 1,799 patients were included in the 0–2- and 0–12-month responder analyses, respectively, and 2,360 patients in the 2–12-month exacerbation rate analysis. At 2 months, 35.1% of patients were FEV1 responders and 44.3% were SGRQ responders. The probability of response was significantly greater with budesonide/formoterol than with formoterol or placebo for both parameters. Two-month responders had a greater chance of 12-month response than 2-month nonresponders for both FEV1 (odds ratio, 5.57; 95% confidence interval, 4.14–7.50) and SGRQ (odds ratio, 3.87; 95% confidence interval, 2.83–5.31). Two-month response in FEV1 (P<0.001), but not SGRQ (P=0.11), was associated with greater reductions in exacerbation risk.
Early FEV1 and SGRQ treatment responses relate to their changes at 12 months. FEV1 response, but not SGRQ response, at 2 months predicts the risk of a future COPD exacerbation in some, but not all patients. This is potentially useful in clinical practice, although more sensitive and specific markers of favorable treatment response are required.
PMCID: PMC4772946  PMID: 26952309
anti-inflammatories; bronchodilator effect; chronic obstructive pulmonary disease; predictors; risk assessment; risk factors
12.  A score to predict short-term risk of COPD exacerbations (SCOPEX) 
There is no clinically useful score to predict chronic obstructive pulmonary disease (COPD) exacerbations. We aimed to derive this by analyzing data from three existing COPD clinical trials of budesonide/formoterol, formoterol, or placebo in patients with moderate-to-very-severe COPD and a history of exacerbations in the previous year.
Predictive variables were selected using Cox regression for time to first severe COPD exacerbation. We determined absolute risk estimates for an exacerbation by identifying variables in a binomial model, adjusting for observation time, study, and treatment. The model was further reduced to clinically useful variables and the final regression coefficients scaled to obtain risk scores of 0–100 to predict an exacerbation within 6 months. Receiver operating characteristic (ROC) curves and the corresponding C-index were used to investigate the discriminatory properties of predictive variables.
The best predictors of an exacerbation in the next 6 months were more COPD maintenance medications prior to the trial, higher mean daily reliever use, more exacerbations during the previous year, lower forced expiratory volume in 1 second/forced vital capacity ratio, and female sex. Using these risk variables, we developed a score to predict short-term (6-month) risk of COPD exacerbations (SCOPEX). Budesonide/formoterol reduced future exacerbation risk more than formoterol or as-needed short-acting β2-agonist (salbutamol).
SCOPEX incorporates easily identifiable patient characteristics and can be readily applied in clinical practice to target therapy to reduce COPD exacerbations in patients at the highest risk.
PMCID: PMC4315304  PMID: 25670896
chronic obstructive pulmonary disease; exacerbation; model; predictor; inhaled corticosteroids; bronchodilators
13.  Insight into Best Variables for COPD Case Identification: A Random Forests Analysis 
This study is part of a larger, multi-method project to develop a questionnaire for identifying undiagnosed cases of chronic obstructive pulmonary disease (COPD) in primary care settings, with specific interest in the detection of patients with moderate to severe airway obstruction or risk of exacerbation.
To examine 3 existing datasets for insight into key features of COPD that could be useful in the identification of undiagnosed COPD.
Random forests analyses were applied to the following databases: COPD Foundation Peak Flow Study Cohort (N=5761), Burden of Obstructive Lung Disease (BOLD) Kentucky site (N=508), and COPDGene® (N=10,214). Four scenarios were examined to find the best, smallest sets of variables that distinguished cases and controls:(1) moderate to severe COPD (forced expiratory volume in 1 second [FEV1] <50% predicted) versus no COPD; (2) undiagnosed versus diagnosed COPD; (3) COPD with and without exacerbation history; and (4) clinically significant COPD (FEV1<60% predicted or history of acute exacerbation) versus all others.
From 4 to 8 variables were able to differentiate cases from controls, with sensitivity ≥73 (range: 73–90) and specificity >68 (range: 68–93). Across scenarios, the best models included age, smoking status or history, symptoms (cough, wheeze, phlegm), general or breathing-related activity limitation, episodes of acute bronchitis, and/or missed work days and non-work activities due to breathing or health.
Results provide insight into variables that should be considered during the development of candidate items for a new questionnaire to identify undiagnosed cases of clinically significant COPD.
PMCID: PMC4729451  PMID: 26835508
COPD; chronic airways obstruction; primary care; screening; case identification; data mining; random forests
14.  A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry 
BMC Genetics  2015;16:138.
Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532).
Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10−11), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10−10); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10−9), 9 [DBH] (p-value = 9.69 × 10−9) and 19 [CYP2A6/7] (p-value = 3.49 × 10−8) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10−9), 4 [FAM13A] (p-value = 3.88 × 10−12), 11 [MMP3/12] (p-value = 3.29 × 10−10) and 14 [RIN3] (p-value = 5.64 × 10−9).
In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0299-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4668640  PMID: 26634245
Chronic obstructive pulmonary disease; DBH; FEV1; FEV1/FVC; Genome-wide association study; Spirometry
15.  Common Genetic Variants Associated with Resting Oxygenation in Chronic Obstructive Pulmonary Disease 
Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10−5) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10−8). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.
PMCID: PMC4224086  PMID: 24825563
chronic obstructive pulmonary disease; hypoxemia; pulse oximetry; genome-wide association study; oxygen saturation
16.  Pneumothorax Risk Factors in Smokers with and without Chronic Obstructive Pulmonary Disease 
Rationale: The demographic, physiological, and computed tomography (CT) features associated with pneumothorax in smokers with and without chronic obstructive pulmonary disease (COPD) are not clearly defined.
Objectives: We evaluated the hypothesis that pneumothorax in smokers is associated with male sex, tall and thin stature, airflow obstruction, and increased total and subpleural emphysema.
Methods: The study included smokers with and without COPD from the COPDGene Study, with quantitative chest CT analysis. Pleural-based emphysema was assessed on the basis of local histogram measures of emphysema. Pneumothorax history was defined by subject self-report.
Measurements and Main Results: Pneumothorax was reported in 286 (3.2%) of 9,062 participants. In all participants, risk of prior pneumothorax was significantly higher in men (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.08–2.22) and non-Hispanic white subjects (OR, 1.90; 95% CI, 1.34–2.69). Risk of prior pneumothorax was associated with increased percent CT emphysema in all participants and participants with COPD (OR, 1.04 for each 1% increase in emphysema; 95% CI, 1.03–1.06). Increased pleural-based emphysema was independently associated with risk of past pneumothorax in all participants (OR, 1.05 for each 1% increase; 95% CI, 1.01–1.10). In smokers with normal spirometry, risk of past pneumothorax was associated with non-Hispanic white race and lifetime smoking intensity (OR, 1.20 for every 10 pack-years; 95% CI, 1.09–1.33).
Conclusions: Among smokers, pneumothorax is associated with male sex, non-Hispanic white race, and increased percentage of total and subpleural CT emphysema. Pneumothorax was not independently associated with height or lung function, even in participants with COPD.
Clinical trial registered with (NCT00608764).
PMCID: PMC4298989  PMID: 25295410
pneumothorax; chronic obstructive pulmonary disease; emphysema
17.  Paradoxical Lung Function Response to Beta2-agonists: Radiologic Correlates and Clinical Implications 
The Lancet. Respiratory medicine  2014;2(11):911-918.
Bronchodilator response is seen in a significant proportion of patients with chronic obstructive pulmonary disease (COPD). However, there are also reports of a paradoxical response (PR) to beta2-agonists, resulting in bronchoconstriction. Asymptomatic bronchoconstriction is likely far more common but there has been no systematic study of this phenomenon.We assessed theprevalence of PR in current and former smokers with and without COPD, and its radiologic correlates and clinical implications.
Subjects from a large multicenter study (COPDGene) were categorized into two groups based on PR defined as at least a 12% and 200mLreduction in FEV1 and/or FVC after administration of a short-acting beta2-agonist (180ucg albuterol). Predictors of PR and associations with respiratory morbidity and computed tomographic measures of emphysema and airway disease were assessed.
9986 subjects were included. PR was seen in 4.54% and the frequency was similar in those with COPD and smokers without airflow obstruction. Compared to Caucasians, PR was twice as common in African-Americans (6.9% vs. 3.4%;p <0.001). On multivariate analyses, African- American race (adjusted OR 1.89, 95%CI 1.50 to 2.39), lesspercent emphysema (OR 0.96, 95%CI 0.92 to 0.99) and increased wall-area% of segmental airways (OR 1.04,95%CI 1.01 to 1.08) were independently associated with PR.PR was independently associated with worse dyspnea, lower six-minute-walk distance, higher BODE index, and a greater frequency of exacerbations(increased by a factor of 1.35, 95%CI 1.003 to 1.81).
Paradoxical response to beta2-agonists is associated with respiratory morbidity and is more common in African Americans.
PMCID: PMC4306040  PMID: 25217076
Paradoxical; bronchodilator; beta 2-agonist; COPD
18.  Reliever salbutamol use as a measure of exacerbation risk in chronic obstructive pulmonary disease 
Debate exists regarding which endpoints most sensitively reflect day-to-day variation in chronic obstructive pulmonary disease (COPD) symptoms and are most useful in clinical practice to predict COPD exacerbations. We hypothesized that short-acting β2-agonist (SABA) reliever use would predict short- and long-term exacerbation risk in COPD patients.
We performed a retrospective analysis of data from a study ( registration: NCT00419744) comparing budesonide/formoterol 320/9 μg with formoterol 9 μg (both twice daily) in patients with moderate-to-very-severe COPD; reliever salbutamol 90 μg was provided. First occurrence of reliever use >4 (low), >10 (medium), and >20 (high) inhalations/day was assessed as a predictor of short-term (3-week) exacerbation risk. Mean daily reliever use in the week preceding the 2-month visit was investigated as a predictor of the long-term (10-month) exacerbation risk, using intervals of 2–5, 6–9, and ≥10 inhalations/day.
Overall, 810 patients were included (61 % male; mean age 63.2 years; post-bronchodilator forced expiratory volume in 1 s 37.7 % of predicted). First occurrence of low, medium, or high reliever use was predictive of an exacerbation within the following 3 weeks; exacerbation risk increased significantly with increasing reliever use. Mean reliever use over 1 week was predictive of long-term exacerbation risk. Patients with mean use of 2–5, 6–9, and ≥10 inhalations/day exhibited 21 %, 67 %, and 135 % higher exacerbation rates, respectively, in the following 10 months, compared with <2 inhalations/day. Budesonide/formoterol was associated with lower short- and long-term exacerbation risk than formoterol in all reliever-use groups.
SABA reliever use is a predictor of short- and long-term exacerbation risk in moderate-to-very-severe COPD patients with a history of exacerbations receiving budesonide/formoterol or formoterol.
PMCID: PMC4546184  PMID: 26293575
COPD; Budesonide/formoterol; Exacerbation; Reliever medication; Predictor
19.  The clinical and genetic features of the COPD asthma overlap syndrome 
The European respiratory journal  2014;44(2):341-350.
Individuals with COPD and asthma are an important but poorly characterized group. The genetic determinants of COPD-asthma overlap have not been studied.
Identify clinical features and genetic risk factors for COPD-asthma overlap.
Subjects were current or former smoking non-Hispanic whites (NHW) or African-Americans (AA) with COPD. Overlap subjects reported a history of physician-diagnosed asthma before the age of 40. We compared clinical and radiographic features between COPD and overlap subjects. We performed genome-wide association studies (GWAS) in the NHW and AA populations, and combined these results in a meta-analysis.
More women and African Americans reported a history of asthma. Overlap subjects had more severe and more frequent respiratory exacerbations, less emphysema, and greater airway wall thickness compared to subjects with COPD alone. The NHW GWAS identified SNPs in CSMD1 (rs11779254, P=1.57×10−6) and SOX5(rs59569785, P=1.61×10−6) and the meta-analysis identified SNPs in the gene GPR65 (rs6574978, P=1.18×10−7) associated with COPD-asthma overlap.
Overlap subjects have more exacerbations, less emphysema and more airway disease for any degree of lung function impairment compared to COPD alone. We identified novel genetic variants associated with this syndrome. COPD-asthma overlap is an important syndrome and may require distinct clinical management.
PMCID: PMC4154588  PMID: 24876173
20.  Identifying Patients with Undiagnosed COPD in Primary Care Settings: Insight from Screening Tools and Epidemiologic Studies 
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, yet research suggests this disease is greatly underdiagnosed. This literature review sought to summarize the most common and significant variables associated with case-finding or missed cases of COPD to inform more effective and efficient detection of high-risk COPD patients in primary care.
PubMed and EMBASE were searched for articles describing case-finding and epidemiologic research to detect or characterize new cases of COPD. International studies in primary and non-primary care settings, published in English from 2002–2014, were eligible for inclusion. Studies related to risk factors for development of COPD were excluded.
Of the 33 studies identified and reviewed, 21 were case-finding or screening and 12 were epidemiological, including cross-sectional, longitudinal, and retrospective designs. A range of variables were identified within and across studies. Variables common to both screening and epidemiological studies included age, smoking status, and respiratory symptoms. Seven significant predictors from epidemiologic studies did not appear in screening tools. No studies targeted discovery of higher risk patients such as those with reduced lung function or risks for exacerbations.
Variables used to identify new cases of COPD or differentiate COPD cases and non-cases are wide- ranging, (from sociodemographic to self-reported health or health history variables), providing insight into important factors for case identification. Further research is underway to develop and test the best, smallest variable set that can be used as a screening tool to identify people with undiagnosed, high-risk COPD in primary care.
PMCID: PMC4521771  PMID: 26236776
chronic obstructive pulmonary disease; primary care; screening; literature review
21.  Cluster Analysis in the COPDGene Study Identifies Subtypes of Smokers with Distinct Patterns of Airway Disease and Emphysema 
Thorax  2014;69(5):416-423.
There is notable heterogeneity in the clinical presentation of patients with COPD. To characterize this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene Study.
We applied a clustering method, k-means, to data from 10,192 smokers in the COPDGene Study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set.
We identified four clusters that can be characterized as 1) relatively resistant smokers (i.e. no/mild obstruction and minimal emphysema despite heavy smoking), 2) mild upper zone emphysema predominant, 3) airway disease predominant, and 4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations).
Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.
PMCID: PMC4004338  PMID: 24563194
22.  Identifying cases of undiagnosed, clinically significant COPD in primary care: qualitative insight from patients in the target population 
Many cases of chronic obstructive pulmonary disease (COPD) are diagnosed only after significant loss of lung function or during exacerbations.
This study is part of a multi-method approach to develop a new screening instrument for identifying undiagnosed, clinically significant COPD in primary care.
Subjects with varied histories of COPD diagnosis, risk factors and history of exacerbations were recruited through five US clinics (four pulmonary, one primary care). Phase I: Eight focus groups and six telephone interviews were conducted to elicit descriptions of risk factors for COPD, recent or historical acute respiratory events, and symptoms to inform the development of candidate items for the new questionnaire. Phase II: A new cohort of subjects participated in cognitive interviews to assess and modify candidate items. Two peak expiratory flow (PEF) devices (electronic, manual) were assessed for use in screening.
Of 77 subjects, 50 participated in Phase I and 27 in Phase II. Six themes informed item development: exposure (smoking, second-hand smoke); health history (family history of lung problems, recurrent chest infections); recent history of respiratory events (clinic visits, hospitalisations); symptoms (respiratory, non-respiratory); impact (activity limitations); and attribution (age, obesity). PEF devices were rated easy to use; electronic values were significantly higher than manual (P<0.0001). Revisions were made to the draft items on the basis of cognitive interviews.
Forty-eight candidate items are ready for quantitative testing to select the best, smallest set of questions that, together with PEF, can efficiently identify patients in need of diagnostic evaluation for clinically significant COPD.
PMCID: PMC4532157  PMID: 26028486
23.  Evaluation of the psychometric properties of the Nighttime Symptoms of COPD Instrument 
Nighttime symptoms can negatively impact the quality of life of patients with chronic obstructive pulmonary disease (COPD). The Nighttime Symptoms of COPD Instrument (NiSCI) was designed to measure the occurrence and severity of nighttime symptoms in patients with COPD, the impact of symptoms on nighttime awakenings, and rescue medication use. The objective of this study was to explore item reduction, inform scoring recommendations, and evaluate the psychometric properties of the NiSCI.
COPD patients participating in a Phase III clinical trial completed the NiSCI daily. Item analyses were conducted using weekly mean and single day scores. Descriptive statistics (including percentage of respondents at floor/ceiling and inter-item correlations), factor analyses, and Rasch model analyses were conducted to examine item performance and scoring. Test–retest reliability was assessed for the final instrument using the intraclass correlation coefficient (ICC). Correlations with assessments conducted during study visits were used to evaluate convergent and known-groups validity.
Data from 1,663 COPD patients aged 40–93 years were analyzed. Item analyses supported the generation of four scores. A one-factor structure was confirmed with factor analysis and Rasch analysis for the symptom severity score. Test–retest reliability was confirmed for the six-item symptom severity (ICC, 0.85), number of nighttime awakenings (ICC, 0.82), and rescue medication (ICC, 0.68) scores. Convergent validity was supported by significant correlations between the NiSCI, St George’s Respiratory Questionnaire, and Exacerbations of Chronic Obstructive Pulmonary Disease Tool-Respiratory Symptoms scores.
The results suggest that the NiSCI can be used to determine the severity of nighttime COPD symptoms, the number of nighttime awakenings due to COPD symptoms, and the nighttime use of rescue medication. The NiSCI is a reliable and valid instrument to evaluate these concepts in COPD patients in clinical trials and clinical practice. Scoring recommendations and steps for further research are discussed.
PMCID: PMC4358643  PMID: 25834415
nighttime symptoms; PRO; psychometric validation; COPD
24.  FEV1/FEV6 to Diagnose Airflow Obstruction. Comparisons with Computed Tomography and Morbidity Indices 
Rationale: FVC is a difficult maneuver for many patients, and forced expiratory volume in 6 seconds (FEV6) has been proposed as a surrogate for FVC for the diagnosis of chronic obstructive pulmonary disease (COPD). Previous studies have performed head-to-head comparisons of these thresholds but did not examine their relationships with structural lung disease, symptoms, or exacerbations.
Objectives: To compare FEV1/FEV6 with FEV1/FVC in the diagnosis of COPD-related morbidity and structural lung disease as assessed by CT.
Methods: We analyzed data from a large multicenter cohort study (COPDGene) that included current and former smokers (age 45–80 yr). Accuracy and concordance between the two ratios in diagnosing structural COPD was compared using CT measures of emphysema and airway disease and COPD-related morbidity to assess how the two ratios compare in defining disease.
Results: A total of 10,018 subjects were included. FEV1/FEV6 showed excellent accuracy in diagnosing airflow obstruction using FEV1/FVC < 0.70 as a reference (area under curve, 0.99; 95% confidence interval [CI], 0.989–0.992; P < 0.001). FEV1/FEV6 < 0.73 had the best sum of sensitivity (92.1%; 95% CI, 90.8–92.4) and specificity (97.3%; 95% CI, 97.3–98.1). There was excellent agreement between the two diagnostic cutoffs (κ = 0.90; 95% CI, 0.80–0.91; P < 0.001). In comparison with control subjects and those positive by FEV1/FVC alone, subjects positive by FEV1/FEV6 alone had greater gas trapping and airway wall thickness, worse functional capacity, and a greater number of exacerbations on follow-up. These relationships held true when disease definitions were made using the lower limits of normal.
Conclusions: FEV1/FEV6 can be substituted for FEV1/FVC in diagnosing airflow obstruction and may better predict COPD-related pathology and morbidity.
PMCID: PMC4028741  PMID: 24450777
FEV1/FEV6; spirometry; COPD
25.  Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis 
The Lancet. Respiratory medicine  2014;2(3):214-225.
The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups.
Genome-wide association analysis in COPDGene (non-Hispanic whites and African-Americans) was combined with existing data from the ECLIPSE, NETT/NAS, and GenKOLS (Norway) studies. Analyses were performed both using all moderate-to-severe cases and the subset of severe cases. Top loci not previously described as genome-wide significant were genotyped in the ICGN study, and results combined in a joint meta-analysis.
Analysis of a total of 6,633 moderate-to-severe cases and 5,704 controls confirmed association at three known loci: CHRNA3/CHRNA5/IREB2, FAM13A, and HHIP (10−12 < P < 10−14), and also showed significant evidence of association at a novel locus near RIN3 (overall P, including ICGN = 5•4×10−9). In the severe COPD analysis (n=3,497), the effects at two of three previously described loci were significantly stronger; we also identified two additional loci previously reported to affect gene expression of MMP12 and TGFB2 (overall P = 2•6x10−9 and 8•3×10−9). RIN3 and TGFB2 expression levels were reduced in a set of Lung Tissue Research Consortium COPD lung tissue samples compared with controls.
In a genome-wide study of COPD, we confirmed associations at three known loci and found additional genome-wide significant associations with moderate-to-severe COPD near RIN3 and with severe COPD near MMP12 and TGFB2. Genetic variants, apart from alpha-1 antitrypsin deficiency, increase the risk of COPD. Our analysis of severe COPD suggests additional genetic variants may be identified by focusing on this subgroup.
National Heart, Lung, and Blood Institute; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; US Department of Veterans Affairs.
PMCID: PMC4176924  PMID: 24621683

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