Impact of the metabolic syndrome on cardiopulmonary morbidity and mortality in individuals with lung function impairment: a prospective cohort study of the Danish general population.

Background: Whether the metabolic syndrome plays a role for the prognosis of individuals with lung function impairment (preserved ratio impaired spirometry (PRISm) or airflow limitation) is unclear. We hypothesised that the metabolic syndrome in individuals with lung function impairment is associated with increased cardiopulmonary morbidity and mortality. Methods: The Copenhagen General Population Study was initiated in 2003 based on a random sample of white men and women aged 20-100 years drawn from the Danish general population. The risk of ischemic heart disease/heart failure, respiratory disease, and all-cause mortality was analysed with Cox models adjusted for age, sex, current smoking, and asthma during 15 years of follow-up. Findings: Among 106,845 adults, 86,159 had normal lung function, 6126 had PRISm, and 14,560 had airflow limitation. We observed 10,448 hospital admissions for ischemic heart disease/heart failure, 21,140 for respiratory disease, and 11,125 deaths. Individuals with versus individuals without the metabolic syndrome generally had higher 5-year absolute risk of all outcomes, including within those with normal lung function, mild-moderate-severe PRISm, and very mild-mild-moderate-severe airflow limitation alike. Compared to individuals without the metabolic syndrome and with normal lung function, those with both the metabolic syndrome and severe PRISm had hazard ratios of 3.74 (95% CI: 2.53-5.55; p < 0.0001) for ischemic heart disease/heart failure, 5.02 (3.85-6.55; p < 0.0001) for respiratory disease, and 5.32 (3.76-7.54; p < 0.0001) for all-cause mortality. Corresponding hazard ratios in those with both the metabolic syndrome and severe airflow limitation were 2.89 (2.34-3.58; p < 0.0001) for ischemic heart disease/heart failure, 5.98 (5.28-6.78; p < 0.0001) for respiratory disease, and 4.16 (3.50-4.95; p < 0.0001) for all-cause mortality, respectively. The metabolic syndrome explained 13% and 27% of the influence of PRISm or airflow limitation on ischemic heart disease/heart failure and all-cause mortality. Interpretation: The metabolic syndrome conferred increased risk of cardiopulmonary morbidity and mortality at all levels of lung function impairment. Funding: Danish Lung Foundation, Danish Heart Foundation, Capital Region of Copenhagen, and Boehringer Ingelheim. JV is supported by the NIHR Manchester BRC.

The role of inflammation in anxiety and depression in the European U-BIOPRED asthma cohorts.

BACKGROUND: Growing evidence indicates high comorbid anxiety and depression in patients with asthma. However, the mechanisms underlying this comorbid condition remain unclear. The aim of this study was to investigate the role of inflammation in comorbid anxiety and depression in three asthma patient cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project. METHODS: U-BIOPRED was conducted by a European Union consortium of 16 academic institutions in 11 European countries. A subset dataset from subjects with valid anxiety and depression measures and a large blood biomarker dataset were analysed, including 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy non-smokers (HC). The Hospital Anxiety and Depression Scale was used to measure anxiety and depression and a series of inflammatory markers were analysed by the SomaScan v3 platform (SomaLogic, Boulder, Colo). ANOVA and the Kruskal-Wallis test were used for multiple-group comparisons as appropriate. RESULTS: There were significant group effects on anxiety and depression among the four cohort groups (p < 0.05). Anxiety and depression of SAn and SAs groups were significantly higher than that of MMA and HC groups (p < 0.05. There were significant differences in serum IL6, MCP1, CCL18, CCL17, IL8, and Eotaxin among the four groups (p < 0.05). Depression was significantly associated with IL6, MCP1, CCL18 level, and CCL17; whereas anxiety was associated with CCL17 only (p < 0.05). CONCLUSIONS: The current study suggests that severe asthma patients are associated with higher levels of anxiety and depression, and inflammatory responses may underlie this comorbid condition.

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Genetic Associations and Architecture of Asthma-COPD Overlap.

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Repeated bronchoscopy in health and obstructive lung disease: is the airway microbiome stable?

OBJECTIVE: Little is known concerning the stability of the lower airway microbiome. We have compared the microbiota identified by repeated bronchoscopy in healthy subjects and patients with ostructive lung diseaseases (OLD). METHODS: 21 healthy controls and 41 patients with OLD completed two bronchoscopies. In addition to negative controls (NCS) and oral wash (OW) samples, we gathered protected bronchoalveolar lavage in two fractions (PBAL1 and PBAL2) and protected specimen brushes (PSB). After DNA extraction, we amplified the V3V4 region of the 16S rRNA gene, and performed paired-end sequencing (Illumina MiSeq). Initial bioinformatic processing was carried out in the QIIME-2 pipeline, identifying amplicon sequence variants (ASVs) with the DADA2 algorithm. Potentially contaminating ASVs were identified and removed using the decontam package in R and the sequenced NCS. RESULTS: A final table of 551 ASVs consisted of 19 × 106 sequences. Alpha diversity was lower in the second exam for OW samples, and borderline lower for PBAL1, with larger differences in subjects not having received intercurrent antibiotics. Permutational tests of beta diversity indicated that within-individual changes were significantly lower than between-individual changes. A non-parametric trend test showed that differences in composition between the two exams (beta diversity) were largest in the PSBs, and that these differences followed a pattern of PSB > PBAL2 > PBAL1 > OW. Time between procedures was not associated with increased diversity. CONCLUSION: The airways microbiota varied between examinations. However, there is compositional microbiota stability within a person, beyond that of chance, supporting the notion of a transient airways microbiota with a possibly more stable individual core microbiome.

Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study.

Rationale: New approaches are needed to guide personalized treatment of asthma.Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping.Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma.Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11ß-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers.Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.Clinical trial registered with www.clinicaltrials.gov (NCT01976767).

Acute exacerbations of COPD and risk of lung cancer in COPD patients with and without a history of asthma.

RATIONALE: There is limited knowledge on the effect of acute exacerbations in chronic obstructive pulmonary disease (AECOPD) on lung cancer risk in COPD patients with and without a history of asthma. This study aims to examine whether AECOPD is associated with risk of lung cancer, and whether the effect depends on a history of asthma. METHODS: In the GenKOLS study of 2003-2005, 852 subjects with COPD performed spirometry, and filled out questionnaires on smoking habits, symptoms and disease history. These data were linked to lung cancer data from the Cancer Registry of Norway through 2013. AECOPD, measured at baseline was the main predictor. To quantify differences in lung cancer risk, we performed Cox-proportional hazards regression. We adjusted for sex, age, smoking variables, body mass index, and lung function. MEASUREMENTS AND RESULTS: During follow-up, 8.8% of the subjects with, and 5.9% of the subjects without exacerbations were diagnosed with lung cancer. Cox regression showed a significant increased risk of lung cancer with one or more exacerbations in COPD patients without a history of asthma, HRR = 2.77 (95% CI 1.39-5.52). We found a significant interaction between a history of asthma and AECOPD on lung cancer. CONCLUSIONS: AECOPD is associated with an increased risk of lung cancer in COPD patients without a history of asthma.

Respiratory symptoms and mortality in four general population cohorts over 45 years.

OBJECTIVE: This study assessed the association between respiratory symptoms and mortality in four cohorts of the general population in Norway aged 15-75 years and in selected subgroups in the pooled sample. METHODS: The study comprised 158,702 persons, who were drawn randomly from the Norwegian population register. All subjects received a standardized, self-administered questionnaire on 11 respiratory symptoms between 1972 and 1998, with follow-up of death until December 31, 2017. Analyses were performed on 114,380 respondents. RESULTS: The hazard of death was closely associated with sex, age, and education. The hazard ratios (HR) for death and the 95% confidence intervals (CI) by risk factors were similar in the four cohorts. After adjustment for demographic and environmental, modifiable factors, the HR for death was 1.90 (95% CI 1.80-2.00) for breathlessness score 3, 1.28 (1.21-1.37) for cough/phlegm score 5 and 1.09 (1.05-1.14) for attack of breathlessness/wheeze score 2 compared to the referent (no symptom), respectively. The cough/phlegm score was associated with death in current smokers but not in never smokers or ex-smokers. Breathlessness score was associated with death in men and women. CONCLUSION: Among persons aged 45-75 years, respiratory symptoms were significant predictors of all cause mortality. Education and smoking habits influenced only the associations between coughing and mortality. The associations were independent of study sites.

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern. INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth. FUNDING: US National Institutes of Health, Wellcome Trust.

Complications and discomfort after research bronchoscopy in the MicroCOPD study.

BACKGROUND: Data on discomfort and complications from research bronchoscopy in chronic obstructive pulmonary disease (COPD) and asthma is limited. We present complications and discomfort occurring within a week after bronchoscopy, and investigate personal and procedural risk factors. METHODS: 239 subjects with COPD, asthma or without lung disease underwent research bronchoscopies as part of a microbiome study of the lower airways (the MicroCOPD study). Bronchoscopy was done in the supine position with oral scope insertion with the option of light conscious alfentanil sedation. Sampling consisted of protected specimen brushes, bronchoalveolar lavage, small volume lavage and for some, endobronchial biopsies. Bleeding, desaturation, cough, haemodynamic changes, dyspnoea and other events that required an unplanned intervention or early termination of bronchoscopy were prospectively recorded. Follow-up consisted of a telephone interview where subjects rated discomfort and answered questions about fever sensation and respiratory symptoms in the week following bronchoscopy. RESULTS: An unplanned intervention or early termination of bronchoscopy was required in 25.9% of bronchoscopies. Three subjects (1.3%) experienced potentially severe complications, of which all recovered without sequelae. COPD subjects experienced more dyspnoea than controls. Sedation and lower age was associated with less unplanned intervention or premature termination. About half of the subjects (47.7%) reported fever. Discomfort was associated with postprocedural fever, dread of bronchoscopy, higher score on the COPD Assessment Test and never-smoking. In subjects undergoing more than one bronchoscopy, the first bronchoscopy was often predictive for complications and postprocedural fever in the repeated bronchoscopy. CONCLUSION: Research bronchoscopies were not associated with more complications or discomfort in COPD subjects. 47.7% experienced postbronchoscopy fever sensation, which was associated with discomfort.

Risk factors for lung cancer in COPD - results from the Bergen COPD cohort study.

BACKGROUND: COPD patients have an increased risk of developing lung cancer, but the underlying mechanisms are poorly understood. We aimed to identify risk factors for lung cancer in patients from the Bergen COPD Cohort Study. METHODS: We compared 433 COPD patients with 279 healthy controls, all former or current smokers. All COPD patients had FEV1<80% and FEV1/FVC-ratio<0.7. Baseline predictors were sex, age, spirometry, body composition, smoking history, emphysema assessed by CT, chronic bronchitis, prior exacerbation frequency, Charlson Comorbidity Score, inhalation medication and 44 serum/plasma inflammatory biomarkers. Patients were followed up for 9 years recording incidence of lung cancer. Cox-regression models were fitted for the statistical analyses. The biomarkers were evaluated using principal component analysis. RESULTS: 28 COPD patients and 3 controls developed lung cancer, COPD patients had a significantly higher risk of developing lung cancer, (HR 5.0; 95% CI 1.5-17.1, p < 0.01, adjusted values). Among COPD patients, emphysema (HR 4.4; 1.7-10.8, p < 0.01) and obesity (HR 3.3; 1.3-8.5, p = 0.02) were associated with a higher cancer rate. Use of inhaled steroids was associated with a lower rate (HR 0.4; 0.2-0.9, p = 0.03). Smoking status, pack-years smoked or levels of systemic inflammatory markers, except for interferon gamma-induced protein 10, did not affect the lung cancer rate in patients with COPD. CONCLUSION: Patients with COPD have a higher lung cancer rate compared to healthy controls adjusted for smoking. The presence of emphysema and obesity in COPD predicted a higher lung cancer risk in COPD patients. Systemic inflammation was not associated with increased lung cancer risk.

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

IL-17-high asthma with features of a psoriasis immunophenotype.

BACKGROUND: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. OBJECTIVE: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. METHODS: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17-high and IL-13-high asthma phenotypes. RESULTS: Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17-high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota diversity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and ß-defensin. CONCLUSION: The IL-17-high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.

New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

Reduced lung function predicts mortality and is key to the diagnosis of chronic obstructive pulmonary disease (COPD). In a genome-wide association study in 400,102 individuals of European ancestry, we define 279 lung function signals, 139 of which are new. In combination, these variants strongly predict COPD in independent populations. Furthermore, the combined effect of these variants showed generalizability across smokers and never smokers, and across ancestral groups. We highlight biological pathways, known and potential drug targets for COPD and, in phenome-wide association studies, autoimmune-related and other pleiotropic effects of lung function-associated variants. This new genetic evidence has potential to improve future preventive and therapeutic strategies for COPD.

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

Genome-Wide Association Analysis of Single-Breath DlCO.

DlCO is a widely used pulmonary function test in clinical practice and a particularly useful measure for assessing patients with chronic obstructive pulmonary disease (COPD). We hypothesized that elucidating genetic determinants of DlCO could lead to better understanding of the genetic architecture of COPD. We estimated the heritability of DlCO using common genetic variants and performed genome-wide association analyses in four cohorts enriched for subjects with COPD (COPDGene [Genetic Epidemiology of COPD], NETT [National Emphysema Treatment Trial], GenKOLS [Genetics of Chronic Obstructive Lung Disease study], and TESRA [Treatment of Emphysema With a Gamma-Selective Retinoid Agonist study]) using a combined European ancestry white dataset and a COPDGene African American dataset. We assessed our genome-wide significant and suggestive associations for DlCO in previously reported genome-wide association studies of COPD and related traits. We also characterized associations of known COPD-associated variants and DlCO. We estimated the SNP-based heritability of DlCO in the European ancestry white population to be 22% (P = 0.0004). We identified three genome-wide significant associations with DlCO: variants near TGFB2, CHRNA3, and PDE11A loci (P < 5 × 10-8). In addition, 12 loci were suggestively associated with DlCO in European ancestry white (P < 1 × 10-5 in the combined analysis and P < 0.05 in both COPDGene and GenKOLS), including variants near NEGR1, CADM2, PCDH7, RETREG1, DACT2, NRG1, ANKRD18A, KRT86, NTN4, ARHGAP28, INSR, and PCBP3. Some DlCO-associated variants were also associated with COPD, emphysema, and/or spirometric values. Among 25 previously reported COPD loci, TGFB2, CHRNA3/CHRNA5, FAM13A, DSP, and CYP2A6 were associated with DlCO (P < 0.001). We identified several genetic loci that were significantly associated with DlCO and characterized effects of known COPD-associated loci on DlCO. These results could lead to better understanding of the heterogeneous nature of COPD.

Comparison of two lung cancer screening scores among patients with chronic obstructive pulmonary disease: A community study.

INTRODUCTION: Based on the National Lung Cancer Screening Trial (NLST), guidelines on screening programs for lung cancer have recommended low-dose computed tomography (LDCT). De Torres et al made a score for COPD patients (COPD-LUCSS) to improve their selection criteria. OBJECTIVE: To examine and compare the discriminating value of both scores in a community-based cohort of COPD patients. METHODS: Four hundred and twenty-two ever-smokers with COPD from the GenKOLS study in Bergen were merged with the Cancer Registry of Norway. We divided the patients into groups of high and low risk according to the COPD-LUCSS and the NLST criteria. Cox regression and logistic regression were used to analyse the associations between the scores and lung cancer. We used Harrell's C and area under the curve (AUC) to estimate discriminating values and to compare the models. RESULTS: Hazard ratio for the high risk vs the low risk in the COPD-LUCSS was 3.0 (1.4-6.5 95% CI), P < 0.01. Hazard ratio for the NLST criteria was 2.2 (95% CI 1.1-4.5), P < 0.05. Harrell's C was 0.63 for the COPD-LUCSS and 0.59 for the NLST selection criteria. AUC was 0.61 for COPD-LUCSS and 0.59 for NLST criteria. Comparing tests showed no differences (P = 0.76). CONCLUSION: Although the COPD-LUCSS and the NLST criteria were associated with increased risk of lung cancer, the AUC and Harrell's C values showed that these models have poor discriminating abilities in our cohort of COPD patients. The COPD-LUCSS was not significantly better than the NLST criteria.

Common and Rare Variants Genetic Association Analysis of Cigarettes per Day Among Ever-Smokers in Chronic Obstructive Pulmonary Disease Cases and Controls.

INTRODUCTION: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown. METHODS: We performed genome-wide association analyses for average cigarettes per day (CPD) across the Genetic Epidemiology of COPD (COPDGene) non-Hispanic white (NHW) (n = 6659) and African American (AA) (n = 3260), GenKOLS (the Genetics of Chronic Obstructive Lung Disease) (n = 1671), and ECLIPSE (the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) (n = 1942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status. RESULTS: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p = 1.78 × 10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4, p = 1.95 × 10-6; CYP2A7, p = 7.50 × 10-5; CYP2B6, p = 4.04 × 10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms on chromosome 15q25 were nominally associated with both NHW COPD cases (ß = 0.11, p = 5.58 × 10-4) and controls (ß = 0.12, p = 3.86 × 10-5) For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p = 5.2 × 10-4). CONCLUSIONS: In a large genome-wide association study of both common variants and a gene-based association of rare coding variants in ever-smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls. IMPLICATIONS: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. Although the genetic effect sizes for these single nucleotide polymorphisms on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker.

Dynamic differences in dietary polyunsaturated fatty acid metabolism in sputum of COPD patients and controls.

INTRODUCTION: Disturbances in onset and resolution of inflammation in chronic obstructive pulmonary disease (COPD) are incompletely understood. Dietary polyunsaturated fatty acids (PUFAs) can be converted into lipid mediators here collectively named oxylipins. These include classical eicosanoids, but also pro-resolving mediators. A balanced production of pro-inflammatory and pro-resolving oxylipins is of importance for adequate inflammatory responses and subsequent return to homeostasis. OBJECTIVES: Here we investigated if PUFA metabolism is disturbed in COPD patients. METHODS: Free PUFA and oxylipin levels were measured in induced sputum samples from the Bergen COPD cohort and COPD exacerbation study using liquid chromatography-mass spectrometry. Additionally, effects of whole cigarette smoke on PUFA metabolism in air-liquid interface cultures of primary bronchial epithelial cells were assessed. RESULTS: Significantly lower levels of free alpha-linolenic acid, linoleic acid and eicosapentaenoic acid (EPA) were detected in sputum from stable COPD patients compared to controls. During acute exacerbation (AE), levels of free arachidonic acid and docosapentaenoic acid were higher than in stable COPD patients. Furthermore, levels of omega-3 EPA- and docosahexaenoic acid-derived oxylipins were lower in sputum from stable COPD patients compared to controls. Cyclooxygenase-2-converted mediators were mostly increased during AE. In vitro studies additionally showed that cigarette smoke exposure may also directly contribute to altered epithelial PUFA metabolism, and indirectly by causing airway epithelial remodelling. CONCLUSIONS: Our findings show significant differences in PUFA metabolism in COPD patients compared to controls, further changed during AE. Airway epithelial remodelling may contribute to these changes. These findings provide new insight in impaired inflammatory resolution in COPD.