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Background: The role and impact of chronic cough in individuals with COPD have not been described in the general population. This study hypothesized that comorbid chronic cough is a marker of disease severity in individuals with COPD., Methods: This study identified individuals with COPD and chronic cough, and recorded respiratory symptoms, health-care utilizations, lung function, and inflammatory biomarkers in blood in a nested cohort of 43,271 adults from the Copenhagen General Population Study (CGPS)., Results: Among 43,271 individuals from the general population, 8,181 (19%) experienced COPD, of whom 796 (10%) had chronic cough. Individuals with COPD and chronic cough had a Leicester Cough Questionnaire median (25th-75th percentiles) total score of 17.7 (16.0-18.9), corresponding to 5.9 (5.3-6.3) for the physical domain, 5.6 (4.9-6.3) for the psychological domain, and 6.3 (5.8-6.8) for the social domain. Among individuals with COPD, those with chronic cough vs those without chronic cough more often experienced sputum production (60% vs 8%), wheezing (46% vs 14%), dyspnea (66% vs 38%), chest pain/tightness (9% vs 4%), nighttime dyspnea (8% vs 3%), episodes of acute bronchitis/pneumonias in the last 10 years (45% vs 25%), and ≥ 3 general practitioner visits in the past 12 months (53% vs 37%). Furthermore, these individuals had lower FEV 1 % predicted (81% vs 89%) and FEV 1 /FVC (0.64 vs 0.66), as well as higher levels of high-sensitivity C-reactive protein, fibrinogen, leukocytes, neutrophils, eosinophils, and IgE in blood., Conclusions: Comorbid chronic cough in individuals with COPD is associated with a more severe disease in terms of more respiratory symptoms and health-care utilizations, lower lung function, and increased inflammation in blood., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

The β 2 -adrenergic receptor (ADRB 2 ) is an important regulator of airway smooth muscle tone in chronic obstructive pulmonary disease (COPD). Variants that impair ADRB 2 function could increase disease risk or reduce the response to endogenous and inhaled adrenergic agonists in COPD. We performed a systematic review and three meta-analyses to assess whether three functional variants (Thr164Ile, Arg16Gly, and Gln27Glu) in the ADRB 2 gene are associated with elevated risk of disease or reduced therapeutic response to inhaled β 2 -agonists in COPD. We searched the medical literature from 1966 to 2017 and found 16 relevant studies comprising 85381 study subjects. The meta-analyses found no significant association between ADRB 2 genotype and COPD risk. The summary odds ratios (ORs) for COPD in Thr164Ile homozygotes and heterozygotes were 2.57 (95% confidence interval (CI): 0.54-12.4) and 1.17 (95% CI: 0.96-1.44), respectively. Corresponding summary ORs for COPD in Arg16Gly homozygotes and heterozygotes were 0.97 (95% CI: 0.76-1.22) and 1.01 (95% CI: 0.81-1.26), while summary ORs for COPD in Gln27Glu homozygotes and heterozygotes were 1.00 (95% CI: 0.80-1.25) and 0.94 (95% CI: 0.69-1.24), respectively. When stratified by ethnicity, the summary ORs for COPD did not differ from 1.0 for any of the ADRB 2 variants among Asian, Caucasian, or African populations. We found no consistent associations between ADRB 2 genotype and treatment response to inhaled β 2 -agonists in COPD. This systematic review and meta-analyses found that COPD risk and response to inhaled β 2 -agonists were not associated with Thr164Ile, Arg16Gly, and Gln27Glu genotypes. However, identified cases of Thr164Ile were few, and additional studies of rare ADRB 2 genotypes are required.

Objective: We tested the hypothesis that use of and adherence to maintenance medication is low among individuals in the general population who have chronic obstructive pulmonary disease (COPD) , even in cases of severe and very severe COPD., Design and Participants: We identified 5,812 individuals with COPD from the Copenhagen General Population Study, and classified them according to the Global Initiative for Obstructive Lung Disease (GOLD) airflow limitation grades 1-4. Dispensing of fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists, long-acting anti-cholinergics, or long-acting beta2-agonists was identified in a nationwide registry. Use of medication was defined as medication dispensed during a one-year period , and adherence was calculated from dosages available in one year., Key Results: Use of fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists varied from 2 % to 61 % (p < 0.001, test for trend), long-acting anti-cholinergics varied from 0.4 % to 36 % (p < 0.001), and long-acting beta2-agonists varied from 0.3 % to 11 % (p < 0.001. Among utilizers of these medications, adherence varied from 29 % to 56 % (p < 0.001, test for trend) across GOLD 1-4 for fixed-dose combinations of inhaled corticosteroids with long-acting beta2-agonists, from 51 % to 68 % (p = 0.11) for long-acting anti-cholinergics, and from 25 to 62 % (p = 0.01) for long-acting beta2-agonists., Conclusions: Use of and adherence to maintenance medication for COPD in the general population was associated with the severity of COPD as defined by GOLD, but even in severe and very severe COPD, use and adherence was low.

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations., Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP)., Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10(-9)) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture., Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

Background: We wished to characterize undertreatment in COPD., Methods: Among 5,812 individuals with COPD defined by FEV1/FVC &lt; 0.7 participating in the Copenhagen General Population Study, we identified 920 individuals with FEV1 &lt; 60% predicted. Prescriptions were identified in an all-inclusive nationwide registry. For each individual, we examined treatment with medication in the year before the day of the baseline examination, as well as treatment in the first year after the examination. Multivariable logistic regression analyses were applied in individuals with FEV1 &lt; 60% predicted to identify predictors of treatment in the first year after baseline., Results: Only 30% of individuals with COPD and FEV1 &lt; 60% predicted were treated with medication in the year before the examination, whereas 42.2% were treated with medication in the first year after. Reporting six to 10 previous respiratory infections during the preceding 10 years that required consulting a doctor and/or staying home from work was the strongest predictor of treatment with medication (OR, 7.9; 95% CI, 3.5-19.8; P &lt; .001). Breathlessness, low FEV1, previous admissions with a discharge diagnosis of COPD, and former smoking were also predictors of treatment with medication, whereas comorbidity predicted lack of treatment. In subgroup analysis, among individuals with FEV1 &lt; 50% predicted, visits to the general practitioner and age were additional predictors of treatment, whereas male sex and being a widow/widower predicted lack of treatment., Conclusions: In this study, we observed important characteristics of a major undertreatment in individuals with COPD in the general population. Previous reported respiratory infections were the strongest predictors of treatment with medications, which indicates that most COPD treatment is initiated because of acute exacerbations.

Importance: Exacerbations of respiratory symptoms in chronic obstructive pulmonary disease (COPD) have profound and long-lasting adverse effects on patients., Objective: To test the hypothesis that elevated levels of inflammatory biomarkers in individuals with stable COPD are associated with an increased risk of having exacerbations., Design, Setting, and Participants: Prospective cohort study examining 61,650 participants with spirometry measurements from the Copenhagen City Heart Study (2001-2003) and the Copenhagen General Population Study (2003-2008). Of these, 6574 had COPD, defined as a ratio between forced expiratory volume in 1 second (FEV1) and forced vital capacity below 0.7., Main Outcomes and Measures: Baseline levels of C-reactive protein (CRP) and fibrinogen and leukocyte count were measured in participants at a time when they were not experiencing symptoms of exacerbations. Exacerbations were recorded and defined as short-course treatment with oral corticosteroids alone or in combination with an antibiotic or as a hospital admission due to COPD. Levels of CRP and fibrinogen and leukocyte count were defined as high or low according to cut points of 3 mg/L, 14 μmol/L, and 9 ×10(9)/L, respectively., Results: During follow-up, 3083 exacerbations were recorded (mean, 0.5/participant). In the first year of follow-up, multivariable-adjusted odds ratios for having frequent exacerbations were 1.2 (95% CI, 0.7-2.2; 17 events/1000 person-years) for individuals with 1 high biomarker, 1.7 (95% CI, 0.9-3.2; 32 events/1000 person-years) for individuals with 2 high biomarkers, and 3.7 (95% CI, 1.9-7.4; 81 events/1000 person-years) for individuals with 3 high biomarkers compared with individuals who had no elevated biomarkers (9 events/1000 person-years; trend: P = 2 × 10(-5)). Corresponding hazard ratios using maximum follow-up time were 1.4 (95% CI, 1.1-1.8), 1.6 (95% CI, 1.3-2.2), and 2.5 (95% CI, 1.8-3.4), respectively (trend: P = 1 × 10(-8)). The addition of inflammatory biomarkers to a basic model including age, sex, FEV1 percent predicted, smoking, use of any inhaled medication, body mass index, history of previous exacerbations, and time since most recent prior exacerbation improved the C statistics from 0.71 to 0.73 (comparison: P = 9 × 10(-5)). Relative risks were consistent in those with milder COPD, in those with no history of frequent exacerbations, and in the 2 studies separately. The highest 5-year absolute risks of having frequent exacerbations in those with 3 high biomarkers (vs no high biomarkers) were 62% (vs 24%) for those with Global Initiative for Chronic Obstructive Lung Disease (GOLD) grades C-D (n = 558), 98% (vs 64%) in those with a history of frequent exacerbations (n = 127), and 52% (vs 15%) for those with GOLD grades 3-4 (n = 465)., Conclusions and Relevance: Simultaneously elevated levels of CRP and fibrinogen and leukocyte count in individuals with COPD were associated with increased risk of having exacerbations, even in those with milder COPD and in those without previous exacerbations. Further investigation is needed to determine the clinical value of these biomarkers for risk stratification.

Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = -0.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population., Competing Interests: I have read the journal's policy and have the following conflicts: NMPH has received an unrestricted research grant from Talecris GmbH. The grant money was applied to covering part of the salary costs for GAT. IF has received educational and consultancy fees, research grant (eALTA Award), and travel support from Talecris Biotherapeutics GmbH and Kedrion S.p.A. TR has received fees for consulting once in 2011 by Talecris Biotherapeutics GmbH. ML travels to European Respiratory Society and American Thoracic Society congresses have been funded by Talecris Biotherapeutics GmbH, has performed paid lectures for Kedrion S.p.A., has obtained research funds by Talecris Biotherapeutics GmbH, as well as funds for staff members. All other authors declare no conflict of interest.

Background: MARCO (macrophage receptor with collagenous structure) is a dominant receptor for unopsonized particles and bacteria in the lungs. Reduced function of this receptor due to genetic variation may be associated with susceptibility to chronic obstructive pulmonary disease (COPD) and lung infection., Objectives: To identify novel genetic variants in MARCO that are associated with reduced lung function, or increased risk of COPD or lung infection., Methods: We first screened 760 individuals with extreme lung phenotypes in a large general population study to identify novel variants in the MARCO gene. We next genotyped the entire cohort consisting of 10,604 individuals to assess the clinical relevance of these variants., Results: We identified 4 novel (R124H, K201N, P303L and G340W) and 5 previously described (H101Q, F282S, G319V, K387Q and E511D) non-synonymous variants. When screening the entire cohort for these variants, we found low minor allele frequencies ranging from 0.005 to 5%. None of the individual MARCO genotypes were associated with reduced lung function, or risk of COPD or lung infection. H101Q heterozygotes had an increased odds ratio for sepsis of 2.2 (95% CI: 1.1-4.4) compared to non-carriers, but none of the other MARCO genotypes were associated with the risk of sepsis., Conclusions: We identified 9 non-synonymous variants in the MARCO gene and showed that these variants are not major risk factors for COPD or lung infection in the Danish population. H101Q heterozygotes had increased sepsis risk, but further research is required to confirm this finding. This study is the first to examine genetic variants in MARCO and the risk of COPD and infections in humans., (Copyright © 2012 S. Karger AG, Basel.)

Rationale: Patients with chronic obstructive pulmonary disease (COPD) have evidence of systemic inflammation that may be implicated in the development of comorbidities., Objectives: To test the hypothesis that elevated levels of three inflammatory biomarkers are associated with increased risk of comorbidities in COPD., Methods: We examined 8,656 patients with COPD from two large Danish population studies and during a median 5 years' follow-up recorded hospital admissions due to major comorbidities as endpoints., Measurements and Main Results: We measured baseline C-reactive protein (CRP), fibrinogen, and leukocyte count, and recorded admissions due to ischemic heart disease, myocardial infarction, heart failure, type II diabetes, lung cancer, pneumonia, pulmonary embolism, hip fracture, and depression for all participants. Multifactorially adjusted risk of ischemic heart disease was increased by a factor of 2.19 (95% confidence interval, 1.48-3.23) in individuals with three biomarkers elevated (CRP > 3 mg/L, fibrinogen > 14 μmol/L, and leukocyte count > 9 × 10(9)/L) versus individuals with all three biomarkers at or below these limits. Corresponding hazard ratios were 2.32 (1.34-4.04) for myocardial infarction, 2.63 (1.71-4.04) for heart failure, 3.54 (2.03-6.19) for diabetes, 4.00 (2.12-7.54) for lung cancer, and 2.71 (2.03-3.63) for pneumonia. There were no consistent differences in risk of pulmonary embolism, hip fracture, or depression as a function of these three biomarkers., Conclusions: Simultaneously elevated levels of CRP, fibrinogen, and leukocyte count are associated with a two- to fourfold increased risk of major comorbidities in COPD. These biomarkers may be an additional tool for clinicians to conduct stratified management of comorbidities in COPD.

Rationale: The new Global Initiative for Obstructive Lung Disease (GOLD) stratification of chronic obstructive pulmonary disease (COPD) into categories A, B, C, and D is based on symptoms, level of lung function, and history of exacerbations., Objectives: To investigate the abilities of this stratification to predict the clinical course of COPD., Methods: Two similar population studies were performed in an area of Copenhagen including 6,628 individuals with COPD., Measurements and Main Results: The patients were monitored for an average period of 4.3 years regarding COPD exacerbations, hospital admissions, and mortality. The percentages of individuals experiencing a COPD exacerbation during the first year of observation were 2.2% in group A, 5.8% in group B, 25.1% in group C, and 28.6% in group D. One- and 3-year mortality rates were 0.6 and 3.8%, respectively, in group A, 3.0 and 10.6% in group B, 0.7 and 8.2% in group C, and 3.4 and 20.1% in group D. Groups B and D, characterized by a higher degree of dyspnea than groups A and C, had five to eight times higher mortality from cardiovascular disease and cancer than did groups A and C., Conclusions: The new stratification performs well by identifying individuals at risk of exacerbations. Surprisingly, subgroup B, characterized by more severe dyspnea, had significantly poorer survival than group C, in spite of a higher FEV(1) level. This subgroup warrants special attention, as the poor prognosis could be caused by cardiovascular disease or cancer, requiring additional assessment and treatment.

Background: Mutations in ATP-binding-cassette-member A3 (ABCA3) are related to severe chronic lung disease in neonates and children, but frequency of chronic lung disease due to ABCA3 mutations in the general population is unknown. We tested the hypothesis that individuals heterozygous for ABCA3 mutations have reduced lung function and increased risk of COPD in the general population., Methods: We screened 760 individuals with extreme pulmonary phenotypes and identified three novel (H86Y, A320T, A1086D) and four previously described mutations (E292V, P766S, S1262G, R1474W) in the ABCA3 gene. We genotyped the entire Copenhagen City Heart study (n = 10,604) to assess the clinical importance of these mutations. To validate our findings we genotyped an additional 54,395 individuals from the Copenhagen General Population Study., Results: In the Copenhagen City Heart Study individuals heterozygous for E292V had 5% reduced FEV₁ % predicted compared with noncarriers (t-test: p = 0.008), and an increased odds ratio for COPD of 1.9 (95% CI: 1.1-3.1). In contrast, the A1086D mutation was associated with increased FEVFEV₁ % predicted (p = 0.03). None of the other ABCA3 mutations associated with lung function or COPD risk in the Copenhagen City Heart Study. In the larger Copenhagen General Population Study, and in the two studies combined, E292V heterozygotes did not have reduced lung function or increased risk of COPD (p = 0.11-0.98), while this was the case for the positive controls, surfactant protein-B 121ins2 heterozygotes and α₁-antitrypsin ZZ homozygotes., Conclusion: Our results indicate that partially reduced ABCA3 activity due to E292V is not a major risk factor for reduced lung function and COPD in the general population. This is an important finding as 1.3% in the Danish population has partially reduced ABCA3 function due to E292V.

Introduction: Our goal was to estimate the number of individuals with chronic obstructive pulmonary disease (COPD) in the Capital Region of Denmark and the need of resources required to implement the regional management programme for COPD., Material and Methods: We examined a total of 45,970 participants from the Copenhagen General Population Study (CGPS) using spirometry and a questionnaire., Results: The prevalence of spirometrically defined COPD among individuals older than 40 years of age was 15%, corresponding to 120,000 citizens in the Region. The number of individuals with moderate COPD (forced expiratory volume in one second (FEV1): 50-80% of predicted value) was estimated to approx. 51,000 (6.4%), whereas at least 10,000 (1.3%) were expected to have severe or very severe COPD (FEV1 < 50% of predicted value). Our estimates indicate that more than 26,000 individuals with moderate, severe or very severe COPD in the Region are smokers and that more than 19,000 qualify for physical training. We estimated that approx. 4,000 individuals with severe COPD were not treated with any inhaled medication., Conclusion: The Capital Region of Denmark needs to allocate substantial resources into early detection, rehabilitation and medical treatment of individuals with COPD in order to comply with the intentions of the Region's own management programme for COPD., Funding: The present analyses were sponsored by a grant from the Danish Ministry of Health. The CGPS was supported by the Copenhagen County Foundation, the Danish Medical Research Council and the Boserup Foundation., Trial Registration: not relevant.

Aims: Myocardial infarction is nominally the most important co-morbidity in patients with chronic obstructive pulmonary disease, and the one with the greatest potential for treatment and prevention to improve the overall prognosis of chronic obstructive pulmonary disease patients. We assessed the extent of myocardial infarction and other co-morbidities in individuals with chronic obstructive pulmonary disease in the general population., Methods and Results: We used individual participant data for the entire Danish population from 1980 through 2006, comprising 140 million person-years of follow-up. We used information from four national Danish registries with 100% follow-up and detected ever-diagnosed chronic obstructive pulmonary disease (n = 313,958) and incident cases of a first myocardial infarction (n = 422,344), lung cancer (n = 116,629), hip fracture (n = 53,756), depression (n = 93 038), and diabetes mellitus (n = 292 228). Multivariate adjusted hazard ratios for life-time association with ever-diagnosed chronic obstructive pulmonary disease were 1.26 (95% CI 1.25-1.27) for myocardial infarction, 2.05 (2.03-2.08) for lung cancer, 2.12 (2.07-2.17) for hip fracture, 1.74 (1.70-1.77) for depression, and 1.21 (1.20-1.23) for diabetes mellitus, compared with controls; these risk estimates were highest in women and the youngest age groups. Before the first hospitalization with chronic obstructive pulmonary disease, multivariate adjusted odds ratios were 1.47 (1.44-1.49) for myocardial infarction, 3.68 (3.52-3.84) for lung cancer, 1.16 (1.13-1.18) for hip fracture, 1.88 (1.80-1.96) for depression, and 1.16 (1.13-1.18) for diabetes mellitus, compared with matched controls. Corresponding values after a chronic obstructive pulmonary disease hospitalization were 0.74 (0.73-0.76), 1.48 (1.45-1.51), 1.23 (1.20-1.27), 1.21 (1.18-1.24), and 0.83 (0.81-0.85), respectively., Conclusion: Chronic obstructive pulmonary disease was associated with higher rates of myocardial infarction, lung cancer, diabetes, hip fracture, and depression, but the strength of these associations was modified after a first admission for chronic obstructive pulmonary disease. These associations may be related to common genetic and/or lifestyle/environmental risk factors, and therefore these factors are likely to have an adverse health impact rather than chronic obstructive pulmonary disease per se.

Background: It is unclear whether elevated plasma C reactive protein (CRP) is causally related to chronic obstructive pulmonary disease (COPD). The authors tested the hypothesis that genetically elevated plasma CRP causes COPD using a Mendelian randomisation design., Methods: The authors measured high-sensitivity CRP in plasma, genotyped for four single nucleotide polymorphisms in the CRP gene, and screened for spirometry-defined COPD and hospitalisation due to COPD in 7974 individuals from the Copenhagen City Heart Study and in 32,652 individuals from the Copenhagen General Population Study., Results: Elevated plasma CRP >3 mg/l compared with <1 mg/l was associated with risk estimates of 1.8 and 2.8 for spirometry-based COPD and of 1.6 and 1.8 for hospitalisation due to COPD in the Copenhagen City Heart Study and the Copenhagen General Population Study, respectively. Genotype combinations of the four CRP polymorphisms were associated with up to a 62% increase in plasma CRP. However, these genotype combinations did not associate with increased risk of COPD or hospitalisation due to COPD in either cohort or in the two cohorts combined. On instrumental variable analysis, a doubling of plasma CRP versus a doubling of genetically elevated CRP resulted in ORs for COPD of 1.27 (95% CI 1.25 to 1.30) versus 1.01 (0.81 to 1.26) and for COPD hospitalisation of 1.47 (1.43 to 1.51) versus 0.82(0.59 to 1.13)., Conclusion: Although elevated CRP is related to both a diagnosis of COPD and subsequent hospital admission, genetically elevated plasma CRP is not associated with an increased risk of clinical COPD. This suggests that the association between CRP levels and COPD is not causal.

Rationale: Hereditary surfactant protein-B deficiency is an autosomal recessive disorder that causes fatal respiratory distress syndrome in newborns. Seventy percent of the cases of hereditary surfactant protein-B deficiency are caused by homozygosity for the 121ins2 mutation in the surfactant protein-B gene. Individuals heterozygous for this mutation have partial absence of surfactant protein-B and could be at risk of lung disease when exposed to additional risk factors for impaired surfactant function such as tobacco smoking., Objectives: To test whether individuals heterozygous for the 121ins2 mutation have reduced lung function and increased risk for chronic obstructive pulmonary disease (COPD) among smokers., Methods: We genotyped 47,600 individuals from the adult Danish general population and recorded smoking habits, spirometry, and hospital admissions due to COPD. The study and findings are limited to Danes/Europeans., Measurements and Main Results: We identified 85 individuals heterozygous for the 121ins2 mutation. Smoking interacted statistically with the 121ins2 genotype in predicting FEV(1) % predicted (P = 0.006), FVC % predicted (P = 0.02) and FEV(1)/FVC (P = 0.002), indicating that the effect of genotype differ by smoking status. Among smokers, 121ins2 heterozygous individuals had 9% reduced FEV(1)% predicted (P = 0.0008), 6% reduced FVC % predicted (P = 0.01) and 6% reduced FEV(1)/FVC (P = 0.00007), compared with wild-types. Also among smokers, 121ins2 heterozygous individuals had odds ratios of 2.4 (95% CI, 1.2-4.8) for spirometry-defined COPD and 2.2 (1.0-5.1) for hospitalization due to COPD. Among never-smokers, 121ins2 heterozygous individuals did not differ from wild-types in lung function or risk of COPD., Conclusions: Surfactant protein-B 121ins2 heterozygosity is associated with reduced lung function and increased risk for COPD among smokers.

The angiotensin-converting enzyme (ACE) gene is a potential candidate gene for risk of asthma, COPD, and COPD co-morbidity. In 9034 Danish adults, we determined whether individuals homozygous or heterozygous for the ACE D allele are at greater risk of asthma, COPD, or COPD co-morbidity compared with ACE II homozygous individuals. In the general population, serum ACE activity increased with the number of D alleles (Kruskal-Wallis ANOVA: II vs. ID, p<0.001; ID vs. DD, p<0.001); however, this did not translate into altered risk of asthma or COPD. In the general population, the odds ratio (95% confidence interval) for asthma was 1.2 (0.9-1.4) for ID individuals and 1.2 (0.9-1.5) for DD individuals compared with II individuals. In the general population, the odds ratio for COPD was 0.9 (0.8-1.1) for ID individuals and 1.0 (0.8-1.2) for DD individuals compared with II individuals. Among patients with COPD, the odds ratio for ischemic heart disease was 1.1 (0.8-1.6) for ID individuals and 1.2 (0.8-1.7) for DD individuals compared with II individuals; corresponding odds ratios for hypertension were 1.1 (0.7-1.5) and 0.8 (0.5-1.2), and for low physical activity 0.9 (0.5-1.4) and 0.7 (0.4-1.2). The results were similar upon adjustment for sex, age, smoking status, body mass index, total cholesterol, and ACE inhibitor/angiotensin II type 1 receptor blocker use. These data suggest that lifelong genetically elevated ACE activity is not a major risk factor for asthma or COPD, or for ischemic heart disease, hypertension, and low physical activity in COPD patients.

Introduction: New markers of early disease activity and prognosis are needed in asthma and chronic obstructive pulmonary disease (COPD)., Objective: To identify new markers of asthma and COPD to implement in clinical practice, we genotyped for common genetic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), alpha(1)-antitrypsin, and mannose-binding lectin (MBL) genes, and measured baseline fibrinogen and C-reactive protein (CRP) concentrations in up to 9245 adults randomly selected from the Danish general population., Materials and Methods: Information on diagnoses of asthma and COPD was collected from two Danish National Registers covering all hospital discharges and deaths in the country. This data was correlated with genotyping results to determine risk of obstructive lung disease according to the genetic and biochemical markers studied., Results: The genetic marker, F508del, in the cystic fibrosis gene was associated with increased asthma risk, but aggregating this data in a meta-analysis with results from previous reports, the risk of asthma was only marginally elevated [summary odds ratio (95%CI): 1.3 (1.1-1.6)]. The F508del marker was not associated with COPD [odds ratio: 0.9 (0.4-1.6)]. Our data also suggested a significant role of smoking on fertility in cystic fibrosis/F508del heterozygotes. The risk of COPD was marginally elevated for the genetic markers, MS and MZ, in the alpha(1)-antitrypsin gene [summary odds ratio: MS, 1.2 (1.0-1.4) and MZ, 2.3 (1.6-3.4)], whereas the SZ marker was an important risk factor of COPD [summary odds ratio: 3.3 (1.2-8.6)]. The ZZ genotype is already in clinical use as a genetic marker for early-onset COPD. Our data also suggested ZZ and MZ are associated with reduced blood pressure and MZ with reduced risk of ischemic cardiovascular disease. Genetic deficiency of MBL was not a major risk factor for asthma [relative risk: 1.1 (0.8-1.7)] or COPD [1.4 (0.97-2.0)]. We found increased risk of cardiovascular disease with MBL deficiency, but this result could not be confirmed in a matched case-control study using cases with ischemic cardiovascular disease from Copenhagen University Hospital, Denmark. Elevated serum fibrinogen and CRP levels were biochemical markers of future COPD. In the future after further validation, it is possible that these markers, particularly CRP, can be used to categorize individuals with low, medium, or high risk of COPD, and thus point out patients in need of intensified prevention and treatment for COPD. The association between COPD and elevated fibrinogen and CRP levels suggests that either factor or upstream factors regulating fibrinogen and CRP expression are important players in the pathogenesis of COPD., Conclusion: We have set-up an analysis for diagnosing the SZ and ZZ genotypes at the Department of Clinical Biochemistry at Herlev University Hospital, together with measurement of plasma alpha(1)-antitrypsin levels. This will help clinicians to detect alpha(1)-antitrypsin-deficient individuals with a high risk for COPD, and opens up for early smoking prevention counseling and potential therapy for individuals identified with alpha(1)-antitrypsin deficiency. The F508del marker and genetic variants in the MBL-2 gene cannot at present be used as markers for obstructive lung disease in the Danish general population. To determine whether fibrinogen or CRP is causally related to COPD, we are currently investigating whether genetically reduced levels of fibrinogen and CRP are associated with reduced risk of future COPD.

COPD is a complex disease with multiple pathological components, which we unfortunately tend to ignore when spirometry is used as the only method to evaluate the disorder. Additional measures are needed to allow a more complete and clinically relevant assessment of COPD. The earliest potential risk factors of disease in COPD are variations in the genetic background. Genetic variations are present from conception and can determine lifelong changes in enzyme activities and protein concentrations. In contrast, measurements in blood, sputum, exhaled breath, broncho-alveolar lavage, and lung biopsies may vary substantially over time. This review explores potential markers of early disease and prognosis in COPD by examining genetic markers in the alpha(1)-antitrypsin, cystic fibrosis transmembrane conductance regulator (CFTR), and MBL-2 genes, and by examining the biochemical markers fibrinogen and C-reactive protein (CRP), which correlate with degree of pulmonary inflammation during stable conditions of COPD. Chronic lung inflammation appears to contribute to the pathogenesis of COPD, and markers of this process have promising predictive value in COPD. To implement markers for COPD in clinical practice, besides those already established for the alpha(1)-antitrypsin gene, further research and validation studies are needed.

Rationale: Patients with chronic obstructive pulmonary disease (COPD) have an ongoing systemic inflammation, which can be assessed by measuring serum C-reactive protein (CRP)., Objective: To determine whether increased serum CRP in individuals with airway obstruction predicts future hospitalization and death from COPD., Methods: We performed a cohort study with a median of 8-yr follow-up of 1,302 individuals with airway obstruction selected from the ongoing Copenhagen City Heart Study., Measurements and Main Results: We measured serum CRP at baseline, and recorded COPD admissions and deaths as outcomes. During follow-up, 185 (14%) individuals were hospitalized due to COPD and 83 (6%) died of COPD. Incidences of COPD hospitalization and COPD death were increased in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L (log rank: p < 0.001). After adjusting for sex, age, FEV(1)% predicted, tobacco consumption, and ischemic heart disease, the hazard ratios for hospitalization and death due to COPD were increased at 1.4 (95% confidence interval, 1.0-2.0) and 2.2 (1.2-3.9) in individuals with baseline CRP > 3 mg/L versus < or = 3 mg/L. After close matching for FEV(1)% predicted and adjusting for potential confounders, baseline CRP was, on average, increased by 1.2 mg/L (analysis of variance: p = 0.002) and 4.1 mg/L (p = 0.001) in those who were subsequently hospitalized or died of COPD, respectively. The absolute 10-yr risks for COPD hospitalization and death in individuals with CRP above 3 mg/L were 54 and 57%, respectively, among those older than 70 yr with a tobacco consumption above 15 g/d and an FEV(1)% predicted of less than 50., Conclusions: CRP is a strong and independent predictor of future COPD outcomes in individuals with airway obstruction.

Rationale: Low body mass index (BMI) is a marker of poor prognosis in chronic obstructive pulmonary disease (COPD). In the general population, the harmful effect of low BMI is due to the deleterious effects of a low fat-free mass index (FFMI; fat-free mass/weight(2))., Objectives: We explored distribution of low FFMI and its association with prognosis in a population-based cohort of patients with COPD., Methods: We used data on 1,898 patients with COPD identified in a population-based epidemiologic study in Copenhagen. FFM was measured using bioelectrical impedance analysis. Patients were followed up for a mean of 7 yr and the association between BMI and FFMI and mortality was examined taking age, sex, smoking, and lung function into account., Main Results: The mean FFMI was 16.0 kg/m(2) for women and 18.7 kg/m(2) for men. Among subjects with normal BMI, 26.1% had an FFMI lower than the lowest 10th percentile of the general population. BMI and FFMI were significant predictors of mortality, independent of relevant covariates. Being in the lowest 10th percentile of the general population for FFMI was associated with a hazard ratio of 1.5 (95% confidence interval, 1.2-1.8) for overall mortality and 2.4 (1.4-4.0) for COPD-related mortality. FFMI was also a predictor of overall mortality when analyses were restricted to subjects with normal BMI., Conclusions: FFMI provides information in addition to BMI and assessment of FFM should be considered in the routine assessment of COPD.

Background: Carriers of cystic fibrosis intron-8 5T alleles with high exon-9 skipping could have increased annual lung function decline and increased risk for asthma or chronic obstructive pulmonary disease (COPD)., Methods: We genotyped 9131 individuals from the adult Danish population for cystic fibrosis 5T, 7T, 9T, and F508del alleles, and examined associations between 11 different genotype combinations, and annual FEV1 decline and risk of asthma or COPD., Results: 5T heterozygotes vs. 7T homozygous controls had no increase in annual FEV1 decline, self-reported asthma, spirometry-defined COPD, or incidence of hospitalization from asthma or COPD. In 5T/7T heterozygotes vs. 7T homozygous controls we had 90% power to detect an increase in FEV1 decline of 8 ml, an odds ratio for self-reported asthma and spirometry-defined COPD of 1.9 and 1.7, and a hazard ratio for asthma and COPD hospitalization of 1.8 and 1.6, respectively. Both 5T homozygotes identified in the study showed evidence of asthma, while none of four 5T/F508del compound heterozygotes had severe pulmonary disease. 7T/9T individuals had annual decline in FEV1 of 19 ml compared with 21 ml in 7T homozygous controls (t-test: P = 0.03). 6.7% of 7T homozygotes without an F508del allele in the cystic fibrosis transmembrane conductance regulator gene reported asthma vs. 11% of 7T/9T individuals with an F508del allele (chi2: P = 0.01) and 40% of 7T homozygotes with an F508del allele (P = 0.04). 7T homozygotes with vs. without an F508del allele also had higher incidence of asthma hospitalization (log-rank: P = 0.003); unadjusted and adjusted equivalent hazard ratios for asthma hospitalization were 11 (95%CI: 1.5-78) and 6.3 (0.84-47) in 7T homozygotes with vs. without an F508del allele., Conclusion: Polythymidine 5T heterozygosity is not associated with pulmonary dysfunction or disease in the adult Caucasian population. Furthermore, our results support that F508del heterozygosity is associated with increased asthma risk independently of the 5T allele.

Background: A deteriorating effect of severe alpha(1)-antitrypsin deficiency (ZZ genotype) on lung function is well known, whereas the role of intermediate deficiency (MZ genotype) remains uncertain., Objective: To test the hypothesis that MZ intermediate alpha(1)-antitrypsin deficiency affects pulmonary function and disease., Design: Population-based cohort study with 21-year follow-up., Setting: Copenhagen, Denmark., Participants: 9187 adults randomly selected from the Danish general population., Measurements: Plasma alpha(1)-antitrypsin levels, annual decrease in FEV(1), airway obstruction, and hospitalization and mortality from chronic obstructive pulmonary disease (COPD)., Results: 451 participants (4.9%) carried the MZ genotype. Plasma alpha(1)-antitrypsin levels were 31% lower in MZ heterozygotes than in persons with the MM genotype (Student t -test, P < 0.001). Annual decrease in FEV(1) was 25 mL in MZ heterozygotes and 21 mL in persons with the MM genotype (t -test, P = 0.048). Airway obstruction was found in 19% of MZ heterozygotes compared with 15% of MM carriers (chi-square test, P = 0.023); in a logistic regression analysis adjusted for age, sex, and tobacco consumption, the corresponding odds ratio was 1.3 (CI, 1.0 to 1.7). The incidence of hospitalization and mortality from COPD was 32 cases per 10 000 person-years in persons with the MZ genotype and 22 cases per 10 000 person-years in those with the MM genotype (log-rank test, P = 0.063). In a Cox regression model adjusted for age, sex, tobacco use, and FEV(1) at study entry, relative risk for COPD outcomes in persons with the MZ genotype versus persons with the MM genotype was 1.5 (CI, 1.0 to 2.3). All these results were independent of the S and E alleles in this gene and were not affected by cystic fibrosis Delta F508 heterozygosity., Conclusions: MZ heterozygotes had a slightly greater rate of decrease in FEV(1) and were modestly over-represented among persons with airway obstruction and COPD. In the population at large, MZ heterozygosity may account for a fraction of COPD cases---on the order of 2%, similar to the percentage of persons with COPD who have the severe but rare ZZ genotype.