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1.  Differences in Adjustment between Individuals with Alpha-1 Antitrypsin Deficiency (AATD) Associated COPD and Non-AATD COPD 
COPD  2013;10(2):226-234.
Smokers who have severe alpha-1 antitrypsin deficiency (AATD) are at risk for developing COPD earlier in life than smokers without AATD, and are likely to experience challenges adjusting to their illness because they are in a highly productive life stage when they are diagnosed with COPD. This study examined whether individuals with AATD-associated COPD differ from individuals with non-AATD COPD with regard to depression, anxiety, dyspnea, and health-related quality of life (HRQL). Cross-sectional data were collected via self-report questionnaires completed by 480 individuals with non-AATD COPD and 578 individuals with AATD-associated COPD under protocols with IRB approval. Multiple linear regression models were used to test whether individuals with non-AATD COPD differed from individuals with AATD-associated COPD with regard to depression, anxiety, dyspnea, and HRQL. All models adjusted for demographic and health characteristics. Individuals with AATD-associated COPD did not report more symptoms of depression or anxiety; however, they did report more dyspnea (B = 0.31, 95% CI = 0.16 to 0.47, p < 0.001) and impairment in HRQL (B = 4.75, 95% CI = 2.10 to 7.41, p < 0.001) than other individuals with COPD. Individuals with AATD-associated COPD were more likely to be a member of a couple (rather than single) and had a higher level of education when compared to individuals with non-AATD COPD. Resources available to persons with AATD-associated COPD, such as being in a serious relationship and having higher education, may offset the effect of age when considering symptoms of depression and anxiety in patients with COPD.
PMCID: PMC3616400  PMID: 23547634
Alpha-1 Antitrypsin Deficiency; Anxiety; Depression; Dyspnea; Health Status; Psychological Adjustment
2.  Gene-environment interactions in chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death throughout the world and is largely associated with cigarette smoking. Despite the appreciation of the central role of smoking in the development of COPD, only a relatively small number of smokers (15%–20%) develop COPD. Recent studies depicting familial aggregation suggest that some subjects may have a genetic predisposition to developing COPD. In this respect, a number of single nucleotide polymorphisms have been reported in association with different COPD features (subphenotypes), although much of this data remains controversial. Classical genetic studies (including twin and family studies) assume an “equal-environment” scenario, but as gene-environment interactions occur in COPD, this assumption needs revision. Thus, new integrated models are needed to examine the major environmental factors associated with COPD which include smoking as well as air pollution, and respiratory infections, and not only genetic predisposition. Revisiting this area, may help answer the question of what has more bearing in the pathogenesis of COPD—the environment or the genomic sequence of the affected subjects. It is anticipated that an improved understanding of this interaction will both enable improved identification of individuals susceptible to developing this disease, as well as improved future treatments for this disease.
PMCID: PMC2629985  PMID: 18990979
chronic obstructive pulmonary disease; environment; genomics; pathogenesis
3.  Early Origins of Child Obesity: Bridging Disciplines and Phases of Development - September 30–October 1, 2010  
This report summarizes a conference: “Early Origins of Child Obesity: Bridging Disciplines and Phases of Development”, held in Chicago on September 30–October 1, 2010. The conference was funded in part by the National Institutes of Health and the Williams Heart Foundation, to achieve the conference objective: forging a next-step research agenda related to the early origins of childhood obesity. This research agenda was to include working with an array of factors (from genetic determinants to societal ones) along a continuum from prenatal life to age 7, with an emphasis on how the developing child deals with the challenges presented by his/her environment (prenatal, parental, nutritional, etc.). The conference offered a unique opportunity to facilitate communication and planning of future work among a variety of researchers whose work separately addresses different periods in early life. Over the span of two days, speakers addressed existing, critical research topics within each of the most-studied age ranges. On the final day, workshops fostered the discussion needed to identify the highest priority research topics related to linking varied early factor domains. These are presented for use in planning future research and research funding.
PMCID: PMC3366610  PMID: 23443002
child obesity; critical periods; early childhood
4.  Assessment of COPD wellness tools for use in primary care: an IPCRG initiative 
COPD is considered a complex disease and global problem that is predicted to be the third most common cause of death by 2030. While managing this chronic condition, primary health care practitioners are faced with the ongoing challenge of achieving good quality of life and overall “wellness” for those affected. As such, a practical tool for monitoring quality of life in a clinical setting is required. However, due to the wide variety of general and disease-specific tools from which to choose, primary health care practitioners are given minimal guidance as to which tool may be most appropriate. To address these challenges, the International Primary Care Respiratory Group (IPCRG) proposed the creation of a user’s guide for primary health care practitioners to assess “wellness” in COPD patients in an everyday clinical setting. This short report outlines the process by which the IPCRG Users’ Guide to COPD “Wellness” Tools was developed. It also describes why this guide has the potential to be of great value in guiding primary health care practitioners to improve patient wellness.
PMCID: PMC3422123  PMID: 22927752
wellness; quality of life; primary care; instrument
5.  SOX5 Is a Candidate Gene for Chronic Obstructive Pulmonary Disease Susceptibility and Is Necessary for Lung Development 
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.
PMCID: PMC3137139  PMID: 21330457
chronic obstructive pulmonary disease; emphysema; knockout mice; lung development; single nucleotide polymorphism
6.  Nicotinic acetylcholine receptor variants associated with susceptibility to chronic obstructive pulmonary disease: a meta-analysis 
Respiratory Research  2011;12(1):158.
Only 10-15% of smokers develop chronic obstructive pulmonary disease (COPD) which indicates genetic susceptibility to the disease. Recent studies suggested an association between COPD and polymorphisms in CHRNA coding subunits of nicotinic acetylcholine receptor. Herein, we performed a meta-analysis to clarify the impact of CHRNA variants on COPD.
We searched Web of Knowledge and Medline from 1990 through June 2011 for COPD gene studies reporting variants on CHRNA. Pooled odds ratios (ORs) were calculated using the major allele or genotype as reference group.
Among seven reported variants in CHRNA, rs1051730 was finally analyzed with sufficient studies. Totally 3460 COPD and 11437 controls from 7 individual studies were pooled-analyzed. A-allele of rs1051730 was associated with an increased risk of COPD regardless of smoking exposure (pooled OR = 1.26, 95% CI 1.18-1.34, p < 10-5). At the genotypic level, the ORs gradually increased per A-allele (OR = 1.27 and 1.50 for GA and AA respectively, p < 10-5). Besides, AA genotype exhibited an association with reduced FEV1% predicted (mean difference 3.51%, 95%CI 0.87-6.16%, p = 0.009) and increased risk of emphysema (OR 1.93, 95%CI 1.29-2.90, p = 0.001).
Our findings suggest that rs1051730 in CHRNA is a susceptibility variant for COPD, in terms of both airway obstruction and parenchyma destruction.
PMCID: PMC3283485  PMID: 22176972
Chronic Obstructive Pulmonary Disease (COPD); Nicotine acetylcholine receptor (nAChR); CHRNA -; ; Single nucleotide polymorphism (SNP)
7.  Evaluation of the Use of Inhaled Medications by Hospital Inpatients with Chronic Obstructive Pulmonary Disease 
The prevalence of chronic obstructive pulmonary disease (COPD) is increasing. Patients with COPD are treated with a variety of inhaled medications. Previous studies evaluating inhaler technique have had varied results but have generally found high rates of misuse of these devices. There is a paucity of studies of inhaler technique focusing on North American patients with COPD who have been admitted to hospital.
To evaluate the inhaler technique of patients with COPD who have been admitted to hospital and to identify baseline patient characteristics and/or inhaler devices associated with poor inhaler technique.
Patients with a diagnosis of COPD who were admitted to the hospitalist or internal medicine service at a tertiary care hospital in British Columbia between October 2010 and April 2011 were identified. After giving informed consent, recruited patients demonstrated their inhaler technique, which was evaluated with standardized checklists. Errors in technique were categorized as either noncritical or critical. Critical errors were defined as those resulting in little or no medication reaching the lungs.
Thirty-seven patients (mean age 78 years) participated in the study. Twenty-two (59%) of the patients made critical errors while demonstrating their inhaler technique. Patients using metered-dose inhalers were more likely to make a critical error than patients using other inhalers (13/14 [93%] versus 9/23 [39%]; relative risk 2.38, p = 0.002). On average, 26% of the steps for using an inhaler were performed incorrectly. Twenty-three (62%) of the patients reported having received previous counselling on inhaler technique, but only 13 (57%) of these 23 patients had received such counselling in the previous 6 months.
More than half of the patients in this study misused their inhaler devices, and many made critical errors that would result in inadequate amounts of drug reaching the lung. Many of the patients were not receiving regular counselling on appropriate inhaler technique. Health care professionals should be aware of poor inhaler technique, should routinely evaluate their patients’ inhaler technique, and should provide counselling.
PMCID: PMC3329903  PMID: 22529403
chronic obstructive pulmonary disease; inhaler technique; metered-dose inhaler; Diskus inhaler; Turbuhaler inhaler; maladie pulmonaire obstructive chronique; technique d’utilisation des inhalateurs; aérosol-doseur; inhalateur Diskus; inhalateur Turbuhaler
8.  Loci Identified by Genome-wide Association Studies Influence Different Disease-related Phenotypes in Chronic Obstructive Pulmonary Disease 
Rationale: Genome-wide association studies have shown significant associations between variants near hedgehog interacting protein HHIP, FAM13A, and cholinergic nicotinic acetylcholine receptor CHRNA3/5 with increased risk of chronic obstructive pulmonary disease (COPD) in smokers; however, the disease mechanisms behind these associations are not well understood.
Objectives: To identify the association between replicated loci and COPD-related phenotypes in well-characterized patient populations.
Methods: The relationship between these three loci and COPD-related phenotypes was assessed in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-point (ECLIPSE) cohort. The results were validated in the family-based International COPD Genetics Network (ICGN).
Measurements and Main Results: The CHRNA3/5 locus was significantly associated with pack-years of smoking (P = 0.002 and 3 × 10−4), emphysema assessed by a radiologist using high-resolution computed tomography (P = 2 × 10−4 and 4.8 × 10−5), and airflow obstruction (P = 0.004 and 1.8 × 10−5) in the ECLIPSE and ICGN populations, respectively. However, variants in the IREB2 gene were only significantly associated with FEV1. The HHIP locus was not associated with smoking intensity but was associated with FEV1/FVC (P = 1.9 × 10−4 and 0.004 in the ECLIPSE and ICGN populations). The HHIP locus was also associated with fat-free body mass (P = 0.007) and with both retrospectively (P = 0.015) and prospectively (P = 0.024) collected COPD exacerbations in the ECLIPSE cohort. Single-nucleotide polymorphisms in the FAM13A locus were associated with lung function.
Conclusions: The CHRNA3/5 locus was associated with increased smoking intensity and emphysema in individuals with COPD, whereas the HHIP and FAM13A loci were not associated with smoking intensity. The HHIP locus was associated with the systemic components of COPD and with the frequency of COPD exacerbations. FAM13A locus was associated with lung function.
PMCID: PMC3029936  PMID: 20656943
COPD exacerbations; nicotine addiction; high-resolution CT; genetic association analysis; emphysema
9.  Association of MMP - 12 polymorphisms with severe and very severe COPD: A case control study of MMPs - 1, 9 and 12 in a European population 
BMC Medical Genetics  2010;11:7.
Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies.
To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history.
Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV.
Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.
PMCID: PMC2820470  PMID: 20078883
10.  How do informal self-care strategies evolve among patients with chronic obstructive pulmonary disease managed in primary care? A qualitative study 
There is much description in the literature of how patients with chronic obstructive pulmonary disease (COPD) manage their breathlessness and engage in self-care activities; however, little of this is from the perspective of those with less severe disease, who are primarily managed in primary care. This study aimed to understand the self-care experiences of patients with COPD who are primarily managed in primary care, and to examine the challenges of engaging in such behaviors.
Semistructured interviews were carried out with 15 patients with COPD as part of a larger project evaluating a self-management intervention. Thematic analysis was supported by NVivo software (version 8, QSR International, Melbourne, Australia).
Three main themes are described, ie, experiencing and understanding symptoms of COPD, current self-care activities, and the importance of family perceptions in managing COPD.
Self-care activities evolved spontaneously as participants experienced symptoms of COPD. However, there was a lack of awareness about whether these strategies would impact upon symptoms. Perceptions of COPD by family members posed a challenge to self-care for some participants. Health care professionals should elicit patients’ prior disease experiences and utilize spontaneous attempts at disease management in future self-management. These findings have implications for promoting self-management and enhancing quality of life.
PMCID: PMC3942113  PMID: 24600218
chronic obstructive pulmonary disease; self-care; qualitative interviews; primary care
11.  Pathogenic triad in COPD: oxidative stress, protease–antiprotease imbalance, and inflammation 
Patients with chronic obstructive pulmonary disease (COPD) exhibit dominant features of chronic bronchitis, emphysema, and/or asthma, with a common phenotype of airflow obstruction. COPD pulmonary physiology reflects the sum of pathological changes in COPD, which can occur in large central airways, small peripheral airways, and the lung parenchyma. Quantitative or high-resolution computed tomography is used as a surrogate measure for assessment of disease progression. Different biological or molecular markers have been reported that reflect the mechanistic or pathogenic triad of inflammation, proteases, and oxidants and correspond to the different aspects of COPD histopathology. Similar to the pathogenic triad markers, genetic variations or polymorphisms have also been linked to COPD-associated inflammation, protease–antiprotease imbalance, and oxidative stress. Furthermore, in recent years, there have been reports identifying aging-associated mechanistic markers as downstream consequences of the pathogenic triad in the lungs from COPD patients. For this review, the authors have limited their discussion to a review of mechanistic markers and genetic variations and their association with COPD histopathology and disease status.
PMCID: PMC3157944  PMID: 21857781
senescence; apoptosis; chronic obstructive pulmonary disease; bronchitis; emphysema
12.  Association Between Single-Nucleotide Polymorphisms in Interleukin-12A and Risk of Chronic Obstructive Pulmonary Disease 
DNA and Cell Biology  2012;31(9):1475-1479.
Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction due to chronic bronchitis, emphysema, and/or disease of small airways. It has been reported that the genetic variation may play a role in the development and severity of COPD. The purpose of this study was to investigate whether single-nucleotide polymorphisms (SNP) in interleukin (IL)-12A and IL-12B were associated with COPD in a Chinese population. The IL-12A rs2243115 and IL-12B rs3212227 polymorphisms were genotyped by performing polymerase chain reaction–restriction fragment length polymorphism in 298 patients with COPD and 346 healthy controls. We observed that the frequencies of GT and GT+GG of IL-12A rs2243115 were significantly different from TT in the COPD group and the control group (GT vs. TT: odds ratio [OR]=2.35, 95% confidence interval [CI]=1.55–3.57, p<0.001; GT+GG vs. TT: OR=2.46, 95% CI=1.63–3.71, p<0.001). These data suggest that the IL-12A rs2243115 polymorphism may contribute to genetic susceptibility to COPD in a Chinese population.
Chronic obstructive pulmonary disease is caused by both environmental factors (such as smoking) and underlying genetic polymorphisms. In this article, a role of the proinflammatory cytokine, IL-12, is shown to be associated with the risk of disease.
PMCID: PMC3429285  PMID: 22734699
13.  Barriers to adherence to chronic obstructive pulmonary disease guidelines by primary care physicians 
Even with the dissemination of several clinical guidelines, chronic obstructive pulmonary disease (COPD) remains underdiagnosed and mismanaged by many primary care physicians (PCPs). The objective of this study was to elucidate barriers to consistent implementation of COPD guidelines.
Patients and methods:
A cross-sectional study implemented in July 2008 was designed to assess attitudes and barriers to COPD guideline usage.
Five hundred US PCPs (309 family medicine physicians, 191 internists) were included in the analysis. Overall, 23.6% of the surveyed PCPs reported adherence to spirometry guidelines over 90% of the time; 25.8% reported adherence to guidelines related to long-acting bronchodilator (LABD) use in COPD patients. In general, physicians were only somewhat familiar with COPD guidelines, and internal medicine physicians were significantly more familiar than family physicians (P < 0.05). In a multivariate model controlling for demographics and barriers to guideline adherence, we found significant associations with two tested guideline components. Adherence to spirometry guidelines was associated with agreement with guidelines, confidence in interpreting data, ambivalence to outcome expectancy, and ability to incorporate spirometry into patient flow. Adherence to LABD therapy guidelines was associated with agreement with guidelines and confidence in gauging pharmacologic response.
Adherence to guideline recommendations of spirometry use was predicted by agreement with the recommendations, self-efficacy, perceived outcome expectancy if recommendations were adhered to, and resource availability. Adherence to recommendations of LABD use was predicted by agreement with guideline recommendations and self-efficacy. Increasing guideline familiarity alone may have limited patient outcomes, as other barriers, such as low confidence and outcome expectancy, are more likely to impact guideline adherence.
PMCID: PMC3064423  PMID: 21468169
COPD; primary care; barriers; guideline adoption
14.  Can endobronchial biopsy analysis be recommended to discriminate between asthma and COPD in routine practice? 
Thorax  2004;59(6):488-493.
Background: International guidelines stress the importance of accurately discriminating between asthma and chronic obstructive pulmonary disease (COPD). Although characteristic pathological features have been described for both conditions, their discriminatory power has never been systematically assessed.
Methods: Endobronchial biopsy (EBB) specimens from patients with a clear clinical diagnosis of asthma and COPD (50 per group) were examined by three pathologists in a double blind manner. They were asked to propose a pathological diagnosis of either asthma or COPD and to analyse qualitatively the most frequent abnormalities reported in the literature.
Results: The sensitivity and specificity of EBB ranged from 36% to 48% and from 56% to 79%, respectively. Eosinophils strongly biased the pathological diagnoses in favour of asthma, whereas their estimated prevalence was similar (11–37% in asthma and 13–41% in COPD). Metaplasia (11–39% in COPD, 1–18% in asthma) and epithelial inflammation (28–61% in COPD, 11–38% in asthma) tended to be specific to COPD, whereas epithelial desquamation (80–98% in asthma, 61–88% in COPD) and basement membrane thickening (71–94% in asthma, 53–88% in COPD) tended to be associated with asthma. There was acceptable intra- and inter-observer agreement only for metaplasia and epithelial eosinophils.
Conclusions: Specific histopathological features of asthma and COPD probably exist, but current routine analysis procedures to assess EBB specimens are not sufficiently discriminatory. This might be rectified by improving pathological definitions.
PMCID: PMC1747055  PMID: 15170031
15.  Significance of bioinformatics in research of chronic obstructive pulmonary disease 
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by the progressive deterioration of pulmonary function and increasing airway obstruction, with high morality all over the world. The advent of high-throughput omics techniques provided an opportunity to gain insights into disease pathogenesis and process which contribute to the heterogeneity, and find target-specific and disease-specific therapies. As an interdispline, bioinformatics supplied vital information on integrative understanding of COPD. This review focused on application of bioinformatics in COPD study, including biomarkers searching and systems biology. We also presented the requirements and challenges in implementing bioinformatics to COPD research and interpreted these results as clinical physicians.
PMCID: PMC3285039  PMID: 22185624
bioinformatics; genomics; proteomics; chronic obstructive pulmonary disease; biomarkers
16.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci 
PLoS Genetics  2009;5(3):e1000421.
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.
Author Summary
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association study (GWAS) in COPD. We conducted a GWAS in a homogenous case-control cohort from Norway and evaluated the top 100 single nucleotide polymorphisms in the family-based International COPD Genetics Network. The polymorphisms that showed replication were further evaluated in subjects from the US National Emphysema Treatment Trial and controls from the Normative Aging Study and then in a fourth cohort of extended pedigrees from the Boston Early-Onset COPD population. Two polymorphisms in the α-nicotinic acetylcholine receptor 3/5 locus on chromosome 15 showed unambiguous evidence of association with COPD. This locus has previously been implicated in both smoking behavior and risk of lung cancer, suggesting the possibility of multiple functional polymorphisms in the region or a single polymorphism with wide phenotypic consequences. The hedgehog interacting protein (HHIP) locus on chromosome 4, which is associated with COPD, is also a significant risk locus for COPD.
PMCID: PMC2650282  PMID: 19300482
17.  COPD Surveillance—United States, 1999-2011 
Chest  2013;144(1):284-305.
This report updates surveillance results for COPD in the United States. For 1999 to 2011, data from national data systems for adults aged ≥ 25 years were analyzed. In 2011, 6.5% of adults (approximately 13.7 million) reported having been diagnosed with COPD. From 1999 to 2011, the overall age-adjusted prevalence of having been diagnosed with COPD declined (P = .019). In 2010, there were 10.3 million (494.8 per 10,000) physician office visits, 1.5 million (72.0 per 10,000) ED visits, and 699,000 (32.2 per 10,000) hospital discharges for COPD. From 1999 to 2010, no significant overall trends were noted for physician office visits and ED visits; however, the age-adjusted hospital discharge rate for COPD declined significantly (P = .001). In 2010 there were 312,654 (11.2 per 1,000) Medicare hospital discharge claims submitted for COPD. Medicare claims (1999-2010) declined overall (P = .045), among men (P = .022) and among enrollees aged 65 to 74 years (P = .033). There were 133,575 deaths (63.1 per 100,000) from COPD in 2010. The overall age-adjusted death rate for COPD did not change during 1999 to 2010 (P = .163). Death rates (1999-2010) increased among adults aged 45 to 54 years (P < .001) and among American Indian/Alaska Natives (P = .008) but declined among those aged 55 to 64 years (P = .002) and 65 to 74 years (P < .001), Hispanics (P = .038), Asian/Pacific Islanders (P < .001), and men (P = .001). Geographic clustering of prevalence, Medicare hospitalizations, and deaths were observed. Declines in the age-adjusted prevalence, death rate in men, and hospitalizations for COPD since 1999 suggest progress in the prevention of COPD in the United States.
PMCID: PMC3707177  PMID: 23619732
18.  Genetic predisposition to accelerated decline of lung function in COPD 
Environmental exposures and genetic susceptibility can contribute to lung function decline in chronic obstructive pulmonary disease (COPD). The environmental factors are better known than the genetic factors. One of the commonest reasons of accelerated forced expiratory volume in one second (FEV1) decline in COPD is the continuation of the smoking habit. In addition, COPD patients have frequent acute respiratory infections which can also accelerate the decline of FEV1. All of the gene variants that have been reported in association with accelerated decline of lung function in COPD represent advancement because the findings generate plausible hypotheses about the possible mechanisms by which gene products could accelerate or avert FEV1 decline. Unfortunately, the results have not been consistently replicated and, animal models required to functionally assess the genetic findings, have not yet yielded sufficient data. Genome-wide association studies should provide more definitive results in COPD and other multigenic conditions. Until these studies are reported, the data to date suggest that products encoded by the alpha-1 antitrypsin, some matrix metalloproteinases, and a number of antioxidant genes are associated with accelerated FEV1 decline in COPD. Data on gene variants associated with acute exacerbations of COPD are now emerging.
PMCID: PMC2695610  PMID: 18044683
lung function; COPD; Smoking; genes
19.  Characteristics of Dutch and Swiss primary care COPD patients – baseline data of the ICE COLD ERIC study 
Clinical Epidemiology  2011;3:273-283.
International Collaborative Effort on Chronic Obstructive Lung Disease: Exacerbation Risk Index Cohorts (ICE COLD ERIC) is a prospective cohort study with chronic obstructive pulmonary disease (COPD) patients from Switzerland and The Netherlands designed to develop and validate practical COPD risk indices that predict the clinical course of COPD patients in primary care. This paper describes the characteristics of the cohorts at baseline.
Material and methods
Standardized assessments included lung function, patient history, self-administered questionnaires, exercise capacity, and a venous blood sample for analysis of biomarkers and genetics.
A total of 260 Dutch and 151 Swiss patients were included. Median age was 66 years, 57% were male, 38% were current smokers, 55% were former smokers, and 76% had at least one and 40% had two or more comorbidities with cardiovascular disease being the most prevalent one. The use of any pulmonary and cardiovascular drugs was 84% and 66%, respectively. Although lung function results (median forced expiratory volume in 1 second [FEV1] was 59% of predicted) were similar across the two cohorts, Swiss patients reported better COPD-specific health-related quality of life (Chronic Respiratory Questionnaire) and had higher exercise capacity.
COPD patients in the ICE COLD ERIC study represent a wide range of disease severities and the prevalence of multimorbidity is high. The rich variation in these primary care cohorts offers good opportunities to learn more about the clinical course of COPD.
PMCID: PMC3224633  PMID: 22135502
COPD; exacerbation; health-related quality of life; prediction; prognosis
20.  FAM13A locus in COPD is independently associated with lung cancer – evidence of a molecular genetic link between COPD and lung cancer 
Recent genome-wide association studies have reported a FAM13A variant on chromosome 4q22.1 is associated with lung function and COPD. We examined this variant in a case-control study of current or former smokers with chronic obstructive pulmonary disease (COPD, n = 458), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups. We confirmed the FAM13A variant (rs7671167) confers a protective effect on smoking-related COPD alone (C allele odds ratio [OR] = 0.79, P = 0.013, and CC genotype OR = 0.71, P = 0.024) and those with COPD, both with and without lung cancer (C allele OR = 0.80, P = 0.008, and CC genotype OR = 0.70, P = 0.007). The FAM13A variant also confers a protective effect on lung cancer overall (C allele OR = 0.75, P = 0.002, and CC genotype OR = 0.64, P = 0.003) even after excluding those with co-existing COPD (C allele OR = 0.67, P = 0.0007, and CC genotype OR = 0.58, P = 0.006). This was independent of age, sex, height, lung function, and smoking history. This protective effect was confined to those with nonsmall cell lung cancer (C allele OR = 0.72, P = 0.0009, and CC genotype OR = 0.61, P = 0.003). This study suggests that genetic predisposition to COPD is shared with lung cancer through shared pathogenetic factors such as the 4q22.1 locus implicating the Rho-kinase pathway.
PMCID: PMC3681173  PMID: 23776362
lung cancer; chronic obstructive pulmonary disease; FAM13A; association study; polymorphism; GTPase
21.  Could symptoms and risk factors diagnose COPD? Development of a Diagnosis Score for COPD 
Clinical Epidemiology  2012;4:247-255.
Diagnosing chronic obstructive pulmonary disease (COPD) without spirometry is still a challenge. Our objective in this study was to develop a scale for diagnosis of COPD.
Data were taken from a cross-sectional epidemiological study. After reducing chronic respiratory symptoms, a logistic regression was used to select risk factors for and symptoms of COPD. The rounded coefficients generated a Diagnosis Score for COPD (DS-COPD), which was dichotomized and differentiated between COPD and other individuals with respiratory symptoms.
We constructed a tool for COPD diagnosis with good properties, comprising 12 items. The area under the curve was 0.849; the positive predictive value was 76% if the DS-COPD was >20 and the negative predictive value was 97% if the DS-COPD was <10. A DS-COPD of 10–19 represented a zone mostly suggestive of no COPD (77%). The score was also inversely correlated with forced expiratory volume in 1 second/forced vital capacity.
In this study, a tool for diagnosis of COPD was constructed with good properties for use in the epidemiological setting, mainly in cases of low or high scoring. It would be of particular interest in the primary care setting, where spirometry may not be available. Prospective studies and application in clinical settings would be necessary to validate this scale further.
PMCID: PMC3470455  PMID: 23071403
diagnosis; scale; development; spirometry
22.  Asthma, chronic obstructive pulmonary disease, or both? Diagnostic labeling and spirometry in primary care patients aged 40 years or more 
To describe symptoms and lung function in patients registered with asthma or chronic obstructive pulmonary disease (COPD) in primary care and to examine how spirometry findings fit with general practitioners’ (GPs) diagnoses.
Patients aged ≥40 years with a diagnosis of asthma or COPD registered in the electronic medical record during the previous 5 years were recruited at seven GP offices in Norway in 2009–2010. Registered diagnosis, spirometry results, comorbidity, and reported symptoms were compared.
Among 376 patients, 62% were women. Based on Global Initiative for Chronic Obstructive Lung Diseases criteria, a spirometry diagnosis of COPD could be made in 68.1% of the patients with a previous COPD diagnosis and in 17.1% of those diagnosed with asthma only (P < 0.001). The κ agreement between last clinical diagnosis of COPD and COPD based on spirometry was 0.50. A restrictive spirometry pattern was found in 19.4% and more frequently in patients diagnosed with both asthma and COPD (23.9%) than in patients diagnosed with COPD only (6.8%, P = 0.003).
The ability of GPs to differentiate between asthma and COPD seems to have considerably improved during the last decade, probably due to the dissemination of spirometry and guidelines for COPD diagnosis. A diagnosis of COPD that cannot be confirmed by spirometry represents a challenge in clinical practice, in particular when a restrictive pattern on spirometry is found.
PMCID: PMC3224654  PMID: 22135492
asthma; COPD; diagnosis; primary care
23.  Patient characteristics, treatment patterns, and health outcomes among COPD phenotypes 
Recent literature has suggested that emphysema and chronic bronchitis, traditionally considered to be entities overlapping within chronic obstructive pulmonary disease (COPD), may be distinct disorders. Few studies have examined the differences in patient characteristics and health outcomes between these conditions. This study examined whether COPD phenotypes represent distinct patient populations, in a large nationally representative US sample.
Data were obtained from the 2010 US National Health and Wellness Survey (NHWS). NHWS respondents (n = 75,000) were categorized as a COPD phenotype based on their self-reported diagnosis of COPD only (n = 970), emphysema only (n = 399), or chronic bronchitis only (n = 2071). Phenotypes were compared on demographics, health characteristics, treatment patterns, health outcomes, work productivity, and resource use. Variables were compared using Chi-square and analysis of variance tests for categorical and continuous outcomes, respectively. Health outcomes were also examined using regression modeling, controlling for demographic and health characteristic covariates.
Patients with chronic bronchitis were significantly younger (51.38 years versus 63.24 years for COPD versus 63.30 years for emphysema, P < 0.05) and more likely to be employed (46.98% versus 23.81% for COPD versus 28.33% for emphysema, P < 0.05). Relative to the other phenotypes, patients with chronic bronchitis were also significantly more likely to be female, nonwhite, and to exercise currently (all P < 0.05), and were significantly less likely to be a current or former smoker (P < 0.05). Controlling for demographic and health characteristics, patients self-identified as having COPD only reported significantly worse physical quality of life (adjusted mean 36.69) and health utilities (adjusted mean 0.65) and significantly more absenteeism (adjusted mean 7.08%), presenteeism (adjusted mean 30.73%), overall work impairment (adjusted mean 34.06%), and activity impairment (adjusted mean 46.59%) than the other phenotypes (all P < 0.05).
These results suggest considerable heterogeneity among different COPD phenotypes with respect to demographics, health characteristics, disease characteristics, treatment patterns, and health outcomes. Research aimed at understanding the differences in patient characteristics and disease presentation of these phenotypes could be used to guide treatment recommendations.
PMCID: PMC3514008  PMID: 23226014
chronic obstructive pulmonary disease; emphysema; chronic bronchitis; quality of life; work productivity; health care resource use
24.  The effect of an active implementation of a disease management programme for chronic obstructive pulmonary disease on healthcare utilization - a cluster-randomised controlled trial 
The growing population living with chronic conditions calls for efficient healthcare-planning and effective care. Implementing disease-management-programmes is one option for responding to this demand. Knowledge is scarce about the effect of implementation processes and their effect on patients; only few studies have reported the effectiveness of disease-management-programmes targeting patients with chronic obstructive pulmonary disease (COPD). The objective of this paper was to determine the effect on healthcare-utilization of an active implementation model for a disease-management-programme for patients with one of the major multimorbidity diseases, COPD.
The standard implementation of a new disease-management-programme for COPD was ongoing during the study-period from November 2008 to November 2010 in the Central Denmark Region. We wanted to test a strategy using Breakthrough Series, academic detailing and lists of patients with COPD. It targeted GPs and three hospitals serving approx. 60,000 inhabitants aged 35 or older and included interventions directed at professionals, organisations and patients. The study was a non-blinded block- and cluster-randomised controlled trial with GP-practices as the unit of randomisation. In Ringkoebing-Skjern Municipality, Denmark, 16 GP-practices involving 38 GPs were randomised to either the intervention-group or the control-group. A comparable neighbouring municipality acted as an external-control-group which included nine GP-practices with 25 GPs. An algorithm based on health-registry-data on lung-related contacts to the healthcare-system identified 2,736 patients who were alive at the end of the study-period. The population included in this study counted 1,372 (69.2%) patients who responded to the baseline questionnaire and confirmed their COPD diagnosis; 458 (33.4%) patients were from the intervention-group, 376 (27.4%) from the control-group and 538(39.2%) from the external-control-group. The primary outcome was adherence to the disease-management-programme measured at patient-level by use of specific services from general practice. Secondary outcomes were use of out-of-hours-services, outpatient-clinic, and emergency-department and hospital-admissions.
The intervention practices provided more planned preventive consultations, additional preventive consultations and spirometries than non-intervention practices. A comparison of the development in the intervention practices with the development in the control-practices showed that the intervention resulted in more planned preventive-consultations, fewer conventional consultations and fewer patients admitted without a lung-related-diagnosis.
Use of the active implementation model for the disease-management-programme for COPD changed the healthcare utilization in accordance with the programme.
Trial registration identifier: NCT01228708.
PMCID: PMC3851941  PMID: 24090189
Implementation; Disease management; Healthcare utilization; COPD; Chronic Care Model; RCT
25.  Association of COPD candidate genes with CT emphysema and airway phenotypes in severe COPD 
The principal determining factors influencing the development of the airway disease and emphysema components of COPD have not been clearly defined. Genetic variability in COPD patients might influence the varying degrees of involvement of airway disease and emphysema. Therefore, we investigated genetic association of SNPs in COPD candidate genes for association with emphysema severity and airway wall thickness phenotypes.
Polymorphisms in six candidate genes were analyzed in 379 subjects of the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study with quantitative chest CT data. Genetic association with percent of lung below −950 hounsfield units (LAA950), airway wall thickness (WT), and derived square root wall area of 10 mm internal perimeter airways (SRWA) were investigated.
Three SNPs in EPHX1, five SNPs in SERPINE2, and one SNP in GSTP1 were significantly associated with LAA950. Five SNPs in TGFB1, two SNPs in EPHX1, one SNP in SERPINE2, and two SNPs in ADRB2 were associated with airway wall phenotypes in NETT.
In conclusion, several COPD candidate genes showed evidence for association with airway wall thickness and emphysema severity using CT in a severe COPD population. Further investigation will be required to replicate these genetic associations for emphysema and airway wall phenotypes.
PMCID: PMC3074301  PMID: 20525719
Airway; chronic obstructive pulmonary disease; computed tomography; emphysema; genetic association

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