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BACKGROUND: Emerging data from longitudinal studies suggest that preserved ratio impaired spirometry (PRISm), defined by proportionate reductions in FEV(1) and FVC, is a heterogeneous population with frequent transitions to other lung function categories relative to individuals with normal and obstructive spirometry. Controversy regarding the clinical significance of these transitions exists (eg, whether transitions merely reflect measurement variability or noise). RESEARCH QUESTION: Are individuals with PRISm enriched for transitions associated with substantial changes in lung function? STUDY DESIGN AND METHODS: Current and former smokers enrolled in the Genetic Epidemiology of COPD (COPDGene) study with spirometry available in phases 1 through 3 (enrollment, 5-year follow-up, and 10-year follow-up) were analyzed. Postbronchodilator lung function categories were as follows: PRISm (FEV(1) < 80% predicted with FEV(1)/FVC ratio ≥ 0.7), Global Initiative for Chronic Obstructive Lung Disease grade 0 (FEV(1) ≥ 80% predicted and FEV(1)/FVC ≥ 0.7), and obstruction (FEV(1)/FVC < 0.7). Significant transition status was affirmative if a subject belonged to two or more spirometric categories and had > 10% change in FEV(1) % predicted and/or FVC % predicted between consecutive visits. Ever-PRISm was present if a subject had PRISm at any visit. Logistic regression examined the association between significant transitions and ever-PRISm status, adjusted for age, sex, race, FEV(1) % predicted, current smoking, pack-years, BMI, and ever-positive bronchodilator response. RESULTS: Among subjects with complete data (N = 1,775) over 10.1 ± 0.4 years of follow-up, the prevalence of PRISm remained consistent (10.4%-11.3%) between phases 1 through 3, but nearly one-half of subjects with PRISm transitioned into or out of PRISm at each visit. Among all subjects, 19.7% had a significant transition; ever-PRISm was a significant predictor of significant transitions (unadjusted OR, 10.3; 95% CI, 7.9-13.5; adjusted OR, 14.9; 95% CI, 10.9-20.7). Results were similar with additional adjustment for radiographic emphysema and gas trapping, when lower limit of normal criteria were used to define lung function categories, and when FEV(1) alone (regardless of change in FVC % predicted) was used to define significant transitions. INTERPRETATION: PRISm is an unstable group, with frequent significant transitions to both obstruction and normal spirometry over time. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT000608764; URL: www.clinicaltrials.gov

Rationale: The ability of peripheral blood biomarkers to assess COPD risk and progression is unknown. Genetics and gene expression may capture important aspects of COPD-related biology that predict...

BACKGROUND: Smokers manifest varied phenotypes of pulmonary impairment. RESEARCH QUESTION: Which pulmonary phenotypes are associated with coronary artery disease (CAD) in smokers? STUDY DESIGN AND METHODS: We analyzed data from the University of Pittsburgh COPD Specialized Center for Clinically Oriented Research (SCCOR) cohort (n = 481) and the Genetic Epidemiology of COPD (COPDGene) cohort (n = 2,580). Participants were current and former smokers with > 10 pack-years of tobacco exposure. Data from the two cohorts were analyzed separately because of methodologic differences. Lung hyperinflation was assessed by plethysmography in the SCCOR cohort and by inspiratory and expiratory CT scan lung volumes in the COPDGene cohort. Subclinical CAD was assessed as the coronary artery calcium score, whereas clinical CAD was defined as a self-reported history of CAD or myocardial infarction (MI). Analyses were performed in all smokers and then repeated in those with airflow obstruction (FEV(1) to FVC ratio, < 0.70). RESULTS: Pulmonary phenotypes, including airflow limitation, emphysema, lung hyperinflation, diffusion capacity, and radiographic measures of airway remodeling, showed weak to moderate correlations (r < 0.7) with each other. In multivariate models adjusted for pulmonary phenotypes and CAD risk factors, lung hyperinflation was the only phenotype associated with calcium score, history of clinical CAD, or history of MI (per 0.2 higher expiratory and inspiratory CT scan lung volume; coronary calcium: OR, 1.2; 95% CI, 1.1-1.5; P = .02; clinical CAD: OR, 1.6; 95% CI, 1.1-2.3; P = .01; and MI in COPDGene: OR, 1.7; 95% CI, 1.0-2.8; P = .05). FEV(1) and emphysema were associated with increased risk of CAD (P < .05) in models adjusted for CAD risk factors; however, these associations were attenuated on adjusting for lung hyperinflation. Results were the same in those with airflow obstruction and were present in both cohorts. INTERPRETATION: Lung hyperinflation is associated strongly with clinical and subclinical CAD in smokers, including those with airflow obstruction. After lung hyperinflation was accounted for, FEV(1) and emphysema no longer were associated with CAD. Subsequent studies should consider measuring lung hyperinflation and examining its mechanistic role in CAD in current and former smokers.

Sex and gender differences in lung health and disease are imperative to consider and study if precision pulmonary medicine is to be achieved. The development of reliable COPD biomarkers has been elusive, and the translation of biomarkers to clinical care has been limited. Useful and effective biomarkers must be developed with attention to clinical heterogeneity of COPD; inherent heterogeneity exists related to grouping women and men together in the studies of COPD. Considering sex and gender differences and influences related to -omics may represent progress in susceptibility, diagnostic, prognostic, and therapeutic biomarker development and clinical innovation to improve the lung health of men and women.

Background Secondary polycythemia is associated with cigarette smoking and chronic obstructive pulmonary disease (COPD). However, the prevalence of polycythemia in COPD and the contributing risk factors for polycythemia in COPD have not been extensively studied. Methods We analyzed the presence of secondary polycythemia in current and former smokers with moderate to very severe COPD at the five-year follow-up visit in the observational COPDGene study. We used logistic regression to evaluate the association of polycythemia with age, sex, race, altitude, current smoking status, spirometry, diffusing capacity for carbon monoxide (DLCO), quantitative chest CT measurements (including emphysema, airway wall thickness, and pulmonary artery to aorta diameter ratio), resting hypoxemia, exercise-induced hypoxemia, and long-term oxygen therapy. Results In a total of 1928 COPDGene participants with moderate to very severe COPD, secondary polycythemia was found in 97 (9.2%) male and 31 (3.5%) female participants. In a multivariable logistic model, severe resting hypoxemia (OR 3.50, 95% CI 1.41–8.66), impaired DLCO (OR 1.28 for each 10-percent decrease in DLCO % predicted, CI 1.09–1.49), male sex (OR 3.60, CI 2.20–5.90), non-Hispanic white race (OR 3.33, CI 1.71–6.50), current smoking (OR 2.55, CI 1.49–4.38), and enrollment in the Denver clinical center (OR 4.42, CI 2.38–8.21) were associated with higher risk for polycythemia. In addition, continuous (OR 0.13, CI 0.05–0.35) and nocturnal (OR 0.46, CI 0.21–0.97) supplemental oxygen were associated with lower risk for polycythemia. Results were similar after excluding participants with anemia and participants enrolled at the Denver clinical center. Conclusions In a large cohort of individuals with moderate to very severe COPD, male sex, current smoking, enrollment at the Denver clinical center, impaired DLCO, and severe hypoxemia were associated with increased risk for secondary polycythemia. Continuous or nocturnal supplemental oxygen use were associated with decreased risk for polycythemia.

COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.

Rationale: Smoking results in at least a decade lower life expectancy. Mortality among current smokers is two to three times as high as never smokers. DNA methylation is an epigenetic modification ...

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 1

RATIONALE: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. OBJECTIVES: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. METHODS: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. MEASUREMENTS AND MAIN RESULTS: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV(1)% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV(1) was 3.9% lower (95% confidence interval [CI], −6.55% to −1.26%) and emphysema (the percentage of lung attenuation areas

BACKGROUND AND AIM: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 enters cells via angiotensin-Converti...

BackgroundBody composition measures, specifically low weight or reduced muscle mass, are associated with mortality in COPD, but the effect of longitudinal body composition changes is undefined.Research questionIs the longitudinal loss of fat-free mass (FFM) associated with increased mortality, including in those with initially normal or elevated body composition metrics?Study design and methodsParticipants with complete data for at least one visit in the COPDGene study (n= 9,268) and the ECLIPSE study (n= 1,760) were included and monitored for 12 and 8 years, respectively. Pectoralis muscle area (PMA) was derived from thoracic CT scans and used as a proxy for FFM. A longitudinal mixed submodel for PMA and a Cox proportional hazards submodel for survival were fitted on a joint distribution, using a shared random intercept parameter and Markov chain Monte Carlo parameter estimation.ResultsBoth cohorts demonstrated a left-shifted distribution of baseline FFM, not reflected in BMI, and an increase in all-cause mortality risk associated with longitudinal loss of PMA. For each 1-cm2 PMA loss, mortality increased 3.1%(95%CI, 2.4%-3.7%; P< .001) in COPDGene, and 2.4%(95%CI, 0.9%-4.0%; P< .001) in ECLIPSE. Increased mortality risk was independent of enrollment values for BMI and disease severity [BODE (body mass, airflow obstruction, dyspnea, and exercise capacity) index quartiles] and was significant even in participants with initially greater than average PMA.InterpretationLongitudinal loss of PMA is associated with increased all-cause mortality, regardless of BMI or initial muscle mass. Consideration of novel screening tests and further research into mechanisms contributing to muscle decline may improve risk stratification and identify novel therapeutic targets in ever smokers.

BackgroundChronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome-wide association study approach.MethodsParticipants with COPD (N=4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self-reported unintentional weight loss>5% in the past year or low BMI (BMI&nbsp

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.

Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. Over the past decade, the proliferation of genome-wide association studies, the accessibility of whole-genome sequencing, and the development of novel methods for analyzing genetic variation data have led to a substantial increase in the understanding of genetic variants that play a role in COPD susceptibility and COPD-related phenotypes. COPDGene (Genetic Epidemiology of COPD), a multicenter, longitudinal study of over 10,000 current and former cigarette smokers, has been pivotal to these breakthroughs in understanding the genetic basis of COPD. To date, over 20 genetic loci have been convincingly associated with COPD affection status, with additional loci demonstrating association with COPD-related phenotypes such as emphysema, chronic bronchitis, and hypoxemia. In this review, we discuss the contributions of the COPDGene study to the discovery of these genetic associations as well as the ongoing genetic investigations of COPD subtypes, protein biomarkers, and post–genome-wide association study analysis.

BACKGROUND: Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. OBJECTIVE: To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. METHODS: Epigenome-wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts—Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P < 0.05) for each outcome were combined in a three-cohort meta-analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations. RESULTS: In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q = 0.03) in all cohorts and lower IL12B expression (ρ = 0.34, P = 0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q = 0.04) in all cohorts and higher CORT expression (ρ = 0.20, P = 0.045) in CAMP. CONCLUSION AND CLINICAL RELEVANCE: Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco-methylation can identify novel markers of treatment sensitivity in asthma. CLINICAL TRIAL REGISTRATION: Childhood Asthma Management Program (CAMP) Phases I (Trial), II (CAMPCS), III (CAMPCS/2) and IV (CAMPCS/3) NCT00000575.

The Genetic Epidemiology of COPD (COPDGene) study is a noninterventional, multicenter, longitudinal analysis of > 10,000 subjects, including smokers with a ≥ 10 pack-year history with and without COPD and healthy never smokers. The goal was to characterize disease-related phenotypes and explore associations with susceptibility genes. The subjects were extensively phenotyped with the use of comprehensive symptom and comorbidity questionnaires, spirometry, CT scans of the chest, and genetic and biomarker profiling. The objective of this review was to summarize the major advances in the clinical epidemiology of COPD from the first 10 years of the COPDGene study. We highlight the influence of age, sex, and race on the natural history of COPD, and the impact of comorbid conditions, chronic bronchitis, exacerbations, and asthma/COPD overlap.

Evidence indicates associations between higher optimism and reduced risk of age-related conditions and premature mortality. This suggests optimism is a positive health asset, but research identifying potential biological mechanisms underlying these associations remains limited. One potential pathway is slower cellular aging, which may delay age-related deterioration in health. Data were from the Women’s Health Initiative (WHI) (N=3,298) and the Veterans Affairs Normative Aging Study (NAS) (N=514), and included dispositional and explanatory style optimism measures. We evaluated whether higher optimism was associated with metrics suggestive of less cellular aging, as indicated by two DNA methylation algorithms, intrinsic (IEAA) and extrinsic epigenetic age acceleration (EEAA); these algorithms represent accelerated biologic aging that exceeds chronological age. We used linear regression models to test our hypothesis while considering several covariates (sociodemographics, depressive symptoms, health behaviors). In both cohorts, we found consistently null associations of all measures of optimism with both measures of DNA methylation aging, regardless of covariates considered. For example, in fully-adjusted models, dispositional optimism was not associated with either IEAA (WHI:β=0.02; 95% Confidence Interval [CI]:-0.15-0.20; NAS:β=-0.06; 95% CI:-0.56-0.44) or EEAA (WHI:β=-0.04; 95% CI: -0.26-0.17; NAS:β=-0.17; 95% CI: -0.80-0.46). Higher optimism was not associated with reduced cellular aging as measured in this study.

Asthma is the most common chronic disease in children. Inhaled corticosteroids (ICS) are the first-line treatment for asthma control, but up to one-third of children have a poor treatment response. The mechanism of ICS resistance is poorly understood, and the role of DNA methylation in ICS treatment response is not known. We examined the association between peripheral blood DNA methylation and ICS treatment response in 152 pediatric persistent asthmatics from the Childhood Asthma Management Program. Response to ICS was measured by the percentage change in forced expiratory volume in 1 s (FEV1) 8 weeks after treatment initiation. The top CpG sites with a nominal P value less than 0.001 were correlated with gene expression using Pearson's and partial correlations. In 152 participants, mean±SD age was 9.8±2.0 years and median change in FEV1 after ICS initiation was 4.6% (interquartile range: 10.4%). A total of 545 CpG sites were differentially methylated (nominal P

Rationale: Increasing awareness of the prevalence and significance of Preserved Ratio Impaired Spirometry (PRISm), alternatively known as restrictive or Global Initiative for Chronic Obstructive Lu...

Background Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. Methods sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). Results Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P 1 (P 10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. Conclusions Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 enters cells via angiotensin-Converting Enzyme 2 (ACE2) receptors, highly expressed in nasal epithelium with parallel high infectivity.1,2 The nasal epigenome is in direct contact with the environment and could explain COVID-19 disparities by reflecting social and environmental influences on ACE2 regulation. We collected nasal swabs from anterior nares of 547 children, measured DNA methylation (DNAm), and tested differences at 15 ACE2 CpGs by sex, age, race/ethnicity and epigenetic age. ACE2 CpGs were differentially methylated by sex with 12 sites having lower DNAm (mean = 12.71%) and 3 sites greater DNAm (mean = 1.45%) among females relative to males. We observed differential DNAm at 5 CpGs for Hispanic females (mean absolute difference = 3.22%) and lower DNAm at 8 CpGs for Black males (mean absolute difference = 1.33%), relative to white participants. Longer DNAm telomere length was associated with greater ACE2 DNAm at 11 and 13 CpGs among males (mean absolute difference = 7.86%) and females (mean absolute difference = 8.21%), respectively. Nasal ACE2 DNAm differences could contribute to our understanding COVID-19 severity and disparities reflecting upstream environmental and social influences. Findings need to be confirmed among adults and patients with risk factors for COVID-19 severity.

Men and women have different manifestations of major lung diseases including chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension. Examples of sex differences in different molecular data types have been observed (genetic, transcriptomic, epigenetic, metabolomic), but few studies have harnessed the power of network medicine and systems biology to unravel the complexity of sex differences in lung disease. Men and women respond differently to environmental exposures, likely capturing both gender (societal constructs) and sex (biologic) effects relevant to the lung. Data collection on gender and gender identity has not been routine in genomic studies but must be performed to develop the most comprehensive precision-based network medicine approaches to lung disease. Each layer contributing to complex networks manifests the aggregate influence of gender- and sex-specific signatures, and these should be systemically evaluated. Many emergent properties and biologic pathways uncovered by sex-specific network analyses would be missed by single omic-type analyses alone. Common approaches in precision medicine have generally not considered sex and gender as key organizing principles. Leveraging “big data” will provide the most advanced insights into sex and gender differences in lung health, resilience, and disease.

Background Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV1 progression in current smokers. Research Question Is use of ACEi and ARB associated with less progression of emphysema and FEV1 decline among individuals with COPD or baseline emphysema? Methods Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume Results Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV1 % predicted, 0.83; 95% CI, –0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV1 % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema. Interpretation Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline. Trial Registry ClinicalTrials.gov ; No.: NCT00608764; URL: www.clinicaltrials.gov

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers. Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene(®)) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model. Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women. Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for chronic Obstructive Lung Disease (GOLD) criteria.

Background: Apparent increased female susceptibility to chronic obstructive pulmonary disease (COPD) suggests sex hormones modulate disease pathogenesis. Little is known about associations between multiparity and lung function in smokers. Research Question: We hypothesized that multiparity is associated with lung function and measures of emphysema and airway disease. Study Design and Methods: Utilizing female participants from the 5-year follow up of the COPD Genetic Epidemiology (COPDGene(®)) study we performed multivariable linear regressions to assess the effect of multiparity and number of pregnancies on forced expiratory volume in 1 second (FEV(1)) percentage of predicted (% predicted), FEV(1)/forced vital capacity (FVC), percent emphysema on computed tomography (CT) scans, and Pi10, a measure of airway thickening. We sampled never smokers and those with lower smoking exposure from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 dataset. Results: We included 1820 participants from COPDGene(®) and 418 participants from NHANES (321 never smokers, 97 ever smokers). In COPDGene(®), multiparity (beta coefficient [β] = -3.8, 95% confidence interval [CI]: [-6.5, -1.1], p = 0.005) and higher number of pregnancies were associated with lower FEV(1) % predicted. Multiparity was not associated with percent emphysema or Pi10. In individuals with no or mild obstruction, multiparity was associated with lower FEV(1) % predicted. There was an interaction with multiparity and age on FEV(1) % predicted (p = 0.025). In NHANES, there was no association between multiparity and FEV(1) % predicted in never smokers or the lower smoking exposure group. Interpretation: Multiparity was associated with lower FEV(1) % predicted in current and former smokers in COPDGene(®) study participants. These preliminary results emphasize the importance of smoking abstinence in women of child-bearing age.

Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P − 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Contains fulltext : 220761.pdf (Publisher’s version ) (Open Access) Rationale: The decades-long progression of chronic obstructive pulmonary disease (COPD) renders identifying different trajectories of disease progression challenging.Objectives: To identify subtypes of patients with COPD with distinct longitudinal progression patterns using a novel machine-learning tool called "Subtype and Stage Inference" (SuStaIn) and to evaluate the utility of SuStaIn for patient stratification in COPD.Methods: We applied SuStaIn to cross-sectional computed tomography imaging markers in 3,698 Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1-4 patients and 3,479 controls from the COPDGene (COPD Genetic Epidemiology) study to identify subtypes of patients with COPD. We confirmed the identified subtypes and progression patterns using ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) data. We assessed the utility of SuStaIn for patient stratification by comparing SuStaIn subtypes and stages at baseline with longitudinal follow-up data.Measurements and Main Results: We identified two trajectories of disease progression in COPD: a "Tissue-->Airway" subtype (n = 2,354, 70.4%), in which small airway dysfunction and emphysema precede large airway wall abnormalities, and an "Airway-->Tissue" subtype (n = 988, 29.6%), in which large airway wall abnormalities precede emphysema and small airway dysfunction. Subtypes were reproducible in ECLIPSE. Baseline stage in both subtypes correlated with future FEV1/FVC decline (r = -0.16 [P < 0.001] in the Tissue-->Airway group; r = -0.14 [P = 0.011] in the Airway-->Tissue group). SuStaIn placed 30% of smokers with normal lung function at elevated stages, suggesting imaging changes consistent with early COPD. Individuals with early changes were 2.5 times more likely to meet COPD diagnostic criteria at follow-up.Conclusions: We demonstrate two distinct patterns of disease progression in COPD using SuStaIn, likely representing different endotypes. One third of healthy smokers have detectable imaging changes, suggesting a new biomarker of "early COPD."

Background: Chronic obstructive pulmonary disease (COPD) is a critical public health burden. The neutrophil-to-lymphocyte ratio (NLR) is an inflammation biomarker and predictor for COPD morbidity and mortality; however, its associations with lung function decline and COPD development are incompletely understood. Methods: We performed a longitudinal study of US veterans with >30 years of follow-up to investigate the associations of NLR with lung function, COPD, and the hypomethylation of cg05575921, the top DNA methylation marker of lung function changes in response to tobacco smoking. This study included 7466 visits from 1549 white males each examined up to 13 times during 1982-2018. NLR was estimated based on automated whole blood cell counts, and cg05575921 profile was measured in blood DNA using Illumina 450K BeadChip from a subset of 1228 visits. Findings: A one-unit increase in NLR was associated with a 0∙021-liter, 0∙016-liter, 0∙29%, and 3∙7-liters/min lower FEV1, FVC, FEV1/FVC, and MMEF, respectively (p-values

Background Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross-study learning approach to integrate these individual scores into an ensemble predictor. The methylation-based risk score was associated with CVD time-to-event in a held-out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10-1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58-2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation-based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high-risk individuals who would be missed by alternative risk metrics. This work was supported by the US Department of Agriculture, Agriculture Research Service (8050–51000-098-00D). Dr. Westerman was additionally supported by National Institutes of Health predoctoral training grant 5T32HL069772-14. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. This article was prepared in collaboration with investigators of the WHI but has not been reviewed by the WHI and does not necessarily reflect the opinions of the WHI investigators or the National Heart, Lung, and Blood Institute. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University (Contract No. N01-HC-25195 and HHSN268201500001I). This article was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or National Heart, Lung, and Blood Institute. The LBC 1936 is supported by Age UK (Disconnected Mind program) and the Medical Research Council (MR/M01311/1). Methylation typing in LBC 1936 was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. LBC 1936 work was conducted in the Centre for Cognitive Ageing and Cognitive Epidemiology, which supported Dr. Deary and is supported by the medical Research Council and Biotechnology and Biological Sciences Research Council (MR/K026992/1). Sí

Rationale Chronic obstructive pulmonary disease (COPD) comprises distinct phenotypes, all characterised by airflow limitation. Objectives We hypothesised that somatotype changes – as a surrogate of adiposity – from early adulthood follow different trajectories to reach distinct phenotypes. Methods Using the validated Stunkard's Pictogram, 356 COPD patients chose the somatotype that best reflects their current body build and those at ages 18, 30, 40 and 50 years. An unbiased group-based trajectory modelling was used to determine somatotype trajectories. We then compared the current COPD-related clinical and phenotypic characteristics of subjects belonging to each trajectory. Measurements and main results At 18 years of age, 88% of the participants described having a lean or medium somatotype (estimated body mass index (BMI) between 19 and 23 kg·m−2) while the other 12% a heavier somatotype (estimated BMI between 25 and 27 kg·m−2). From age 18 onwards, five distinct trajectories were observed. Four of them demonstrating a continuous increase in adiposity throughout adulthood with the exception of one, where the initial increase was followed by loss of adiposity after age 40. Patients with this trajectory were primarily females with low BMI and DLCO (diffusing capacity of the lung for carbon monoxide). A persistently lean trajectory was seen in 14% of the cohort. This group had significantly lower forced expiratory volume in 1 s (FEV1), DLCO, more emphysema and a worse BODE (BMI, airflow obstruction, dyspnoea and exercise capacity) score thus resembling the multiple organ loss of tissue (MOLT) phenotype. Conclusions COPD patients have distinct somatotype trajectories throughout adulthood. Those with the MOLT phenotype maintain a lean trajectory throughout life. Smoking subjects with this lean phenotype in early adulthood deserve particular attention as they seem to develop more severe COPD., In smoking-related COPD, somatotype trajectories are associated with the final COPD phenotype. Specifically, the “pink puffer” or multiorgan loss of tissue (MOLT) phenotype occurs where the patient remains lean. https://bit.ly/2YNhwfu

Dawn L DeMeo,1 Sreeram Ramagopalan,2 Abhishek Kavati,3 Ashok Vegesna,3 Meilan K Han,4 Anthony Yadao,5 Teresa K Wilcox,2 Barry J Make6 On behalf of COPDGene Investigators 1Channing Division of Network Medicine and the Pulmonary and Critical Care Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; 2Real-World Evidence, Evidera, London, UK; 3US Health Economics and Outcomes Research, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 4Division of Pulmonary and Critical Care, University of Michigan, Ann Arbor, MI, USA; 5US Clinical Development and Medical Affairs, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 6Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA Background: Previous studies suggest that gender differences exist in COPD diagnosis and symptoms; these differences may be more pronounced in younger adults. Our objective was to explore age-associated gender differences across a range of COPD severities. Materials and methods: A total of 4,484 current and former smokers with COPD from the Genetic Epidemiology of COPD cohort were investigated using regression modeling to explore the association between gender, age, disease severity, and the contributing elements of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification system (symptoms, exacerbation risk, airflow limitation). Results: The age–gender interaction was observed across multiple age categories. Compared to men with COPD, younger women with COPD had a greater likelihood of more severe dyspnea, airflow limitation, greater risk for exacerbations, and categorization in GOLD groups B and D. These differences were less pronounced in older women with COPD. However, older women remained more likely to experience severe dyspnea and to manifest more severe COPD (B vs A) than older men, despite lower pack-years of smoking. Conclusion: These data demonstrate the significant symptom burden of COPD in women, especially younger women. More research is needed to understand the pathogenesis of increased severity of COPD in women and to develop gender-targeted clinical assessment and management approaches to improve outcomes for women and men with COPD at all ages. Keywords: COPD, gender, age, symptoms, exacerbations

COPD likely has developmental origins; however, the underlying molecular mechanisms are not fully identified. Investigation of lung tissue-specific epigenetic modifications such as DNA methylation using network approaches might facilitate insights linking in utero smoke (IUS) exposure and risk for COPD in adulthood.We performed genome-wide methylation profiling for adult lung DNA from 160 surgical samples and 78 fetal lung DNA samples isolated from discarded tissue at 8–18 weeks of gestation. Co-methylation networks were constructed to identify preserved modules that shared methylation patterns in fetal and adult lung tissues and associations with fetal IUS exposure, gestational age and COPD.Weighted correlation networks highlighted preserved and co-methylated modules for both fetal and adult lung data associated with fetal IUS exposure, COPD and lower adult lung function. These modules were significantly enriched for genes involved in embryonic organ development and specific inflammation-related pathways, including Hippo, phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), Wnt, mitogen-activated protein kinase and transforming growth factor-β signalling. Gestational age-associated modules were remarkably preserved for COPD and lung function, and were also annotated to genes enriched for the Wnt and PI3K/AKT pathways.Epigenetic network perturbations in fetal lung tissue exposed to IUS and of early lung development recapitulated in adult lung tissue from ex-smokers with COPD. Overlapping fetal and adult lung tissue network modules highlighted putative disease pathways supportive of exposure-related and age-associated developmental origins of COPD.

Identifying differentially variable (DV) genomic probes is becoming a new approach to detect novel genomic risk factors for complex human diseases. The F test is the standard equal-variance test in statistics. For high-throughput genomic data, the probe-wise F test has been successfully used to detect biologically relevant DNA methylation marks that have different variances between two groups of subjects (e.g., cases versus controls). In addition to DNA methylation, microRNA (miRNA) is another important mechanism of epigenetics. However, to the best of our knowledge, no studies have identified DV miRNAs. In this article, we proposed a novel model-based clustering method to improve the power of the probe-wise F test to detect DV miRNAs. We imposed special structures on covariance matrices for each cluster of miRNAs based on the prior information about the relationship between variances in cases and controls and about the independence among them. Simulation studies showed that the proposed method seems promising in detecting DV probes. Based on two real datasets about human hepatocellular carcinoma (HCC), we identified 7 DV-only miRNAs (hsa-miR-1826, hsa-miR-191, hsa-miR-194-star, hsa-miR-222, hsa-miR-502-3p, hsa-miR-93, and hsa-miR-99b) using the proposed method, one (hsa-miR-1826) of which has not yet been reported to be related to HCC in the literature.

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 (β = 0.11, p = 5.58 × 10(−4)) and controls (β = 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.

Background Previous investigations in adult smokers from the COPDGene Study have shown that early-life respiratory disease is associated with reduced lung function, COPD, and airway thickening. Using 5-year follow-up data, we assessed disease progression in subjects who had experienced early-life respiratory disease. We hypothesized that there are alternative pathways to reaching reduced FEV 1 and that subjects who had childhood pneumonia, childhood asthma, or asthma-COPD overlap (ACO) would have less lung function decline than subjects without these conditions. Methods Subjects returning for 5-year follow-up were assessed. Childhood pneumonia was defined by self-reported pneumonia at Results Follow-up data from 4,915 subjects were examined, including 407 subjects who had childhood pneumonia, 323 subjects who had childhood asthma, and 242 subjects with ACO. History of childhood asthma or ACO was associated with an increased exacerbation frequency (childhood asthma, P P = .006) and odds of severe exacerbations (childhood asthma, OR, 1.41; ACO, OR, 1.42). History of childhood pneumonia was associated with increased exacerbations in subjects with COPD (absolute difference [β], 0.17; P = .04). None of these early-life respiratory diseases were associated with an increased rate of lung function decline or progression on CT scans. Conclusions Subjects who had early-life asthma are at increased risk of developing COPD and of having more active disease with more frequent and severe respiratory exacerbations without an increased rate of lung function decline over a 5-year period. Trial Registry ClinicalTrials.gov; No. NCT00608764; https://clinicaltrials.gov.

BackgroundCigarette smoking is the strongest risk factor for COPD. Smoking burden is frequently measured in pack-years, but the relative contribution of cigarettes smoked per day versus duration towards the development of structural lung disease, airflow obstruction and functional outcomes is not known.MethodsWe analysed cross-sectional data from a large multicentre cohort (COPDGene) of current and former smokers. Primary outcome was airflow obstruction (FEV1/FVC); secondary outcomes included five additional measures of disease: FEV1, CT emphysema, CT gas trapping, functional capacity (6 min walk distance, 6MWD) and respiratory morbidity (St George’s Respiratory Questionnaire, SGRQ). Generalised linear models were estimated to compare the relative contribution of each smoking variable with the outcomes, after adjustment for age, race, sex, body mass index, CT scanner, centre, age of smoking onset and current smoking status. We also estimated adjusted means of each outcome by categories of pack-years and combined groups of categorised smoking duration and cigarettes/day, and estimated linear trends of adjusted means for each outcome by categorised cigarettes/day, smoking duration and pack-years.Results10 187 subjects were included. For FEV1/FVC, standardised beta coefficient for smoking duration was greater than for cigarettes/day and pack-years (P1/FVC with increase in pack-years (regression coefficient β=−0.023±SE0.003; P=0.003) and duration over all ranges of smoking cigarettes/day (β=−0.041±0.004; P1, 6MWD and SGRQ.ConclusionSmoking duration alone provides stronger risk estimates of COPD than the composite index of pack-years.Trial registration numberPost-results; NCT00608764.

Contains fulltext : 194255.pdf (Publisher’s version ) (Open Access) BACKGROUND: Emphysema has considerable variability in its regional distribution. Craniocaudal emphysema distribution is an important predictor of the response to lung volume reduction. However, there is little consensus regarding how to define upper lobe-predominant and lower lobe-predominant emphysema subtypes. Consequently, the clinical and genetic associations with these subtypes are poorly characterized. METHODS: We sought to identify subgroups characterized by upper-lobe or lower-lobe emphysema predominance and comparable amounts of total emphysema by analyzing data from 9,210 smokers without alpha-1-antitrypsin deficiency in the Genetic Epidemiology of COPD (COPDGene) cohort. CT densitometric emphysema was measured in each lung lobe. Random forest clustering was applied to lobar emphysema variables after regressing out the effects of total emphysema. Clusters were tested for association with clinical and imaging outcomes at baseline and at 5-year follow-up. Their associations with genetic variants were also compared. RESULTS: Three clusters were identified: minimal emphysema (n = 1,312), upper lobe-predominant emphysema (n = 905), and lower lobe-predominant emphysema (n = 796). Despite a similar amount of total emphysema, the lower-lobe group had more severe airflow obstruction at baseline and higher rates of metabolic syndrome compared with subjects with upper-lobe predominance. The group with upper-lobe predominance had greater 5-year progression of emphysema, gas trapping, and dyspnea. Differential associations with known COPD genetic risk variants were noted. CONCLUSIONS: Subgroups of smokers defined by upper-lobe or lower-lobe emphysema predominance exhibit different functional and radiological disease progression rates, and the upper-lobe predominant subtype shows evidence of association with known COPD genetic risk variants. These subgroups may be useful in the development of personalized treatments for COPD.

The prevalence of chronic obstructive pulmonary disease (COPD) and its associated comorbidities increase with age. However, little is understood about differences in the disease in patients over 65 years of age compared with younger patients.To determine disease characteristics of COPD and its impact in older patients compared with younger patients.We examined baseline characteristics of patients with COPD (global obstructive lung disease stage II-IV) in 2 large cohorts: Genetic Epidemiology of COPD Study (COPDGene) and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We compared demographics, indices of disease severity, prevalence of comorbidities, exacerbation frequency, and quality of life scores in patients ≥65 years of age vs patients65 years of age. We also tested for associations of age with disease characteristics and health outcomes.In the COPDGene cohort, older patients (n = 1663) had more severe disease as measured by forced expiratory volume in 1 second (1.22 vs 1.52 L, P .001), use of long-term oxygen therapy (35% vs 22%, P .001), 6-minute walk distance (355 vs 375 m, P .001), and radiographic evidence of emphysema (14% vs 8%, P .001) and air trapping (47% vs 36%, P .001) and were more likely to have comorbidities compared with younger patients (n = 2027). Similarly, in the ECLIPSE cohort, older patients (n = 1030) had lower forced expiratory volume in 1 second (1.22 vs 1.34 L, P .001), greater use of long-term oxygen therapy (7% vs 5%, P = .02), shorter 6- minute walk distance (360 vs 389 m, P .001), and more radiographic evidence of emphysema (17% vs 14%, P = .009) than younger patients (n = 1131). In adjusted analyses of both cohorts, older age was associated with decreased frequency of exacerbations [odds ratio = 0.52, 95% confidence interval (CI) = 0.43-0.64 in COPDGene, odds ratio = 0.79, 95% CI = 0.64-0.99 in ECLIPSE] and a better quality of life (lower St. Georges respiratory questionnaire score) (β = -8.7, 95% CI = -10.0 to -7.4 in COPDGene, β = -4.4, 95% CI = -6.1 to -3.2 in ECLIPSE).Despite greater severity of illness, older patients with COPD had better quality of life and reported fewer exacerbations than younger patients. Although this observation needs to be explored further, it may be related to the fact that older patients change their expectations and learn to adapt to their disease.

Background Exercise capacity (EC) and physical activity (PA) are independent, potentially modifiable predictors of clinical outcomes in COPD. Molecular measures of biological age may help characterize variability in EC and PA observed among COPD patients. Methods Veterans with COPD (FEV1/FVC Results Subjects (n = 269) were predominantly male (98.5%), white (92.9%), and elderly (70.6 ± 8.5 years) with average FEV1% of 57.7 ± 21.1, 6MWD of 374.3 ± 93.5 m, and daily steps of 3043.4 ± 2374 at baseline. In adjusted models, multiple measures of baseline epigenetic age and age acceleration were inversely associated with 6MWD; only GrimAge was inversely associated with PA. Longitudinal change in Hannum-Age was inversely associated with change in EC at 12 weeks (n = 94). No measures of biological age were significantly associated with prospective AEs over 1.3 ± 0.3 years. Conclusions Epigenetic measures of biological age are independent predictors of EC and PA, but not AEs, among individuals with COPD.

Background Blood biomarkers are increasingly used to stratify high risk chronic obstructive pulmonary disease (COPD) patients; however, there are fewer studies that have investigated multiple biomarkers and replicated in multiple large well-characterized cohorts of susceptible current and former smokers. Methods We used two MSD multiplex panels to measure 9 cytokines and chemokines in 2123 subjects from COPDGene and 1117 subjects from SPIROMICS. These biomarkers included: interleukin (IL)-2, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, eotaxin/CCL-11, eotaxin-3/CCL-26, and thymus and activation-regulated chemokine (TARC)/CCL-17. Regression models adjusted for clinical covariates were used to determine which biomarkers were associated with the following COPD phenotypes: airflow obstruction (forced expiratory flow at 1 s (FEV1%) and FEV1/forced vital capacity (FEV1/FVC), chronic bronchitis, COPD exacerbations, and emphysema. Biomarker-genotype associations were assessed by genome-wide association of single nucleotide polymorphisms (SNPs). Results Eotaxin and IL-6 were strongly associated with airflow obstruction and accounted for 3–5% of the measurement variance on top of clinical variables. IL-6 was associated with progressive airflow obstruction over 5 years and both IL-6 and IL-8 were associated with progressive emphysema over 5 years. None of the biomarkers were consistently associated with chronic bronchitis or COPD exacerbations. We identified one novel SNP (rs9302690 SNP) that was associated with CCL17 plasma measurements. Conclusion When assessing smoking related pulmonary disease, biomarkers of inflammation such as IL-2, IL-6, IL-8, and eotaxin may add additional modest predictive value on top of clinical variables alone. Trial registration COPDGene (ClinicalTrials.gov Identifier: NCT02445183). Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) (ClinicalTrials.gov Identifier: NCT 01969344). Electronic supplementary material The online version of this article (10.1186/s12931-017-0662-2) contains supplementary material, which is available to authorized users.

Electronic cigarettes (e-cigarettes) are battery-operated nicotine-delivery devices used by some smokers as a cessation tool as well as by never smokers. To determine the usage of e-cigarettes in older adults at risk for or with chronic obstructive pulmonary disease (COPD). Prospective cohorts. COPDGene (N = 3536) and SPIROMICS (N = 1060) subjects who were current or former smokers aged 45–80. Participants were surveyed to determine whether e-cigarette use was associated with longitudinal changes in COPD progression or smoking habits. From 2010 to 2016, participants who had ever used e-cigarettes steadily increased to 12–16%, but from 2014 to 2016 current use was stable at ~5%. E-cigarette use in African-Americans (AA) and whites was similar; however, AA were 1.8–2.9 times as likely to use menthol-flavored e-cigarettes. Current e-cigarette and conventional cigarette users had higher nicotine dependence and consumed more nicotine than those who smoked only conventional cigarettes. E-cigarette users had a heavier conventional cigarette smoking history and worse respiratory health, were less likely to reduce or quit conventional cigarette smoking, had higher nicotine dependence, and were more likely to report chronic bronchitis and exacerbations. Ever e-cigarette users had more rapid decline in lung function, but this trend did not persist after adjustment for persistent conventional cigarette smoking. E-cigarette use, which is common in adults with or at risk for COPD, was associated with worse pulmonary-related health outcomes, but not with cessation of smoking conventional cigarettes. Although this was an observational study, we find no evidence supporting the use of e-cigarettes as a harm reduction strategy among current smokers with or at risk for COPD.

Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across three cohorts: Women’s Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort, and used a recently-introduced cross-study learning approach to integrate these individual predictions into an ensemble predictor. The methylation-based risk score (MRS) predicted CVD time-to-event in a held-out fraction of the Framingham dataset (HR per SD = 1.28, p = 2e-3) and predicted myocardial infarction status in the independent REGICOR dataset (OR per SD = 2.14, p = 9e-7). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged dataset. Additionally, we investigated interactions between the MRS and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced predictive power in those with less traditional risk factor elevation. This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that the DNA methylation data may enable the discovery of high-risk individuals that would be missed by alternative risk metrics.