Publications by authors named "Craig P Hersh"

160 Publications

An interferon inducible signature of airway disease from blood gene expression profiling.

Eur Respir J 2021 Oct 14. Epub 2021 Oct 14.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Background: The molecular basis of airway remodeling in chronic obstructive pulmonary disease remains poorly understood. We identified gene expression signatures associated with chest CT scan airway measures to understand molecular pathways associated with airway disease.

Methods: In 2,396 subjects in the COPDGene Study, we examined the relationship between quantitative CT airway phenotypes and blood transcriptomes to identify airway disease-specific genes and to define an airway wall thickness (AWT) gene set score. Multivariable regression analyses were performed to identify associations of the AWT score with clinical phenotypes, bronchial gene expression and genetic variants.

Results: Type 1 interferon induced genes were consistently associated with airway wall thickness, Pi10, and wall area percent, with the strongest enrichment in airway wall thickness. A score derived from 18 genes whose expression was associated with AWT was associated with COPD-related phenotypes including reduced lung function (FEV% predicted -3.4, p<0.05) and increased exacerbations (incidence rate ratio 1.6, p<0.05). The AWT score was reproducibly associated with airway wall thickness in bronchial samples from 23 subjects (beta 3.22, p<0.05). The blood AWT score was associated with genetic variant rs876039, an expression quantitative trait locus (eQTL) for 1, a gene which regulates interferon signaling and is associated with inflammatory diseases.

Conclusion: A gene expression signature with interferon stimulated genes from peripheral blood and bronchial brushings is associated with CT airway wall thickness, lung function, and exacerbations. Shared genes and genetic associations suggest viral responses and/or autoimmune dysregulation as potential underlying mechanisms of airway disease in COPD.
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http://dx.doi.org/10.1183/13993003.00569-2021DOI Listing
October 2021

Peripheral blood microbial signatures in current and former smokers.

Sci Rep 2021 Oct 6;11(1):19875. Epub 2021 Oct 6.

Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA.

The human microbiome has a role in the development of multiple diseases. Individual microbiome profiles are highly personalized, though many species are shared. Understanding the relationship between the human microbiome and disease may inform future individualized treatments. We hypothesize the blood microbiome signature may be a surrogate for some lung microbial characteristics. We sought associations between the blood microbiome signature and lung-relevant host factors. Based on reads not mapped to the human genome, we detected microbial nucleic acids through secondary use of peripheral blood RNA-sequencing from 2,590 current and former smokers with and without chronic obstructive pulmonary disease (COPD) from the COPDGene study. We used the Genome Analysis Toolkit (GATK) microbial pipeline PathSeq to infer microbial profiles. We tested associations between the inferred profiles and lung disease relevant phenotypes and examined links to host gene expression pathways. We replicated our analyses using a second independent set of blood RNA-seq data from 1,065 COPDGene study subjects and performed a meta-analysis across the two studies. The four phyla with highest abundance across all subjects were Proteobacteria, Actinobacteria, Firmicutes and Bacteroidetes. In our meta-analysis, we observed associations (q-value < 0.05) between Acinetobacter, Serratia, Streptococcus and Bacillus inferred abundances and Modified Medical Research Council (mMRC) dyspnea score. Current smoking status was associated (q < 0.05) with Acinetobacter, Serratia and Cutibacterium abundance. All 12 taxa investigated were associated with at least one white blood cell distribution variable. Abundance for nine of the 12 taxa was associated with sex, and seven of the 12 taxa were associated with race. Host-microbiome interaction analysis revealed clustering of genera associated with mMRC dyspnea score and smoking status, through shared links to several host pathways. This study is the first to identify a bacterial microbiome signature in the peripheral blood of current and former smokers. Understanding the relationships between systemic microbial signatures and lung-related phenotypes may inform novel interventions and aid understanding of the systemic effects of smoking.
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http://dx.doi.org/10.1038/s41598-021-99238-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494912PMC
October 2021

Multiethnic genome-wide and HLA association study of total serum IgE level.

J Allergy Clin Immunol 2021 Sep 15. Epub 2021 Sep 15.

Department of Human Genetics, University of Chicago, Chicago, Ill.

Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE.

Objective: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901).

Methods: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data.

Results: We identified 6 loci at genome-wide significance (P < 5 × 10), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (P = 2 × 10; P = 5 × 10; P = 4 × 10), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (P = 8 × 10).

Conclusion: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.
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http://dx.doi.org/10.1016/j.jaci.2021.09.011DOI Listing
September 2021

Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease.

J Cachexia Sarcopenia Muscle 2021 Sep 15. Epub 2021 Sep 15.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Chronic 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.

Methods: Participants 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 < 20 kg/m ). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non-Hispanic White (NHW) participants with COPD. Single variant and gene-based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein-protein interaction (PPI) data.

Results: At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3-5.6, P = 3.2 × 10 ) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane-bound protein ephrin-A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin-responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene-based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling.

Conclusions: The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.
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http://dx.doi.org/10.1002/jcsm.12782DOI Listing
September 2021

Multi-omics subtyping pipeline for chronic obstructive pulmonary disease.

PLoS One 2021 25;16(8):e0255337. Epub 2021 Aug 25.

Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.

Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of mortality in the United States; however, COPD has heterogeneous clinical phenotypes. This is the first large scale attempt which uses transcriptomics, proteomics, and metabolomics (multi-omics) to determine whether there are molecularly defined clusters with distinct clinical phenotypes that may underlie the clinical heterogeneity. Subjects included 3,278 subjects from the COPDGene cohort with at least one of the following profiles: whole blood transcriptomes (2,650 subjects); plasma proteomes (1,013 subjects); and plasma metabolomes (1,136 subjects). 489 subjects had all three contemporaneous -omics profiles. Autoencoder embeddings were performed individually for each -omics dataset. Embeddings underwent subspace clustering using MineClus, either individually by -omics or combined, followed by recursive feature selection based on Support Vector Machines. Clusters were tested for associations with clinical variables. Optimal single -omics clustering typically resulted in two clusters. Although there was overlap for individual -omics cluster membership, each -omics cluster tended to be defined by unique molecular pathways. For example, prominent molecular features of the metabolome-based clustering included sphingomyelin, while key molecular features of the transcriptome-based clusters were related to immune and bacterial responses. We also found that when we integrated the -omics data at a later stage, we identified subtypes that varied based on age, severity of disease, in addition to diffusing capacity of the lungs for carbon monoxide, and precent on atrial fibrillation. In contrast, when we integrated the -omics data at an earlier stage by treating all data sets equally, there were no clinical differences between subtypes. Similar to clinical clustering, which has revealed multiple heterogenous clinical phenotypes, we show that transcriptomics, proteomics, and metabolomics tend to define clusters of COPD patients with different clinical characteristics. Thus, integrating these different -omics data sets affords additional insight into the molecular nature of COPD and its heterogeneity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255337PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386883PMC
August 2021

Hedgehog interacting protein-expressing lung fibroblasts suppress lymphocytic inflammation in mice.

JCI Insight 2021 Sep 8;6(17). Epub 2021 Sep 8.

Channing Division of Network Medicine, and.

Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking and characterized by chronic inflammation in vulnerable individuals. However, it is unknown how genetic factors may shape chronic inflammation in COPD. To understand how hedgehog interacting protein, encoded by HHIP gene identified in the genome-wide association study in COPD, plays a role in inflammation, we utilized Hhip+/- mice that present persistent inflammation and emphysema upon aging similar to that observed in human COPD. By performing single-cell RNA sequencing of the whole lung from mice at different ages, we found that Hhip+/- mice developed a cytotoxic immune response with a specific increase in killer cell lectin-like receptor G1-positive CD8+ T cells with upregulated Ifnγ expression recapitulating human COPD. Hhip expression was restricted to a lung fibroblast subpopulation that had increased interaction with CD8+ T lymphocytes in Hhip+/- compared with Hhip+/+ during aging. Hhip-expressing lung fibroblasts had upregulated IL-18 pathway genes in Hhip+/- lung fibroblasts, which was sufficient to drive increased levels of IFN-γ in CD8+ T cells ex vivo. Our finding provides insight into how a common genetic variation contributes to the amplified lymphocytic inflammation in COPD.
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http://dx.doi.org/10.1172/jci.insight.144575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492352PMC
September 2021

Haemoglobin as a biomarker for clinical outcomes in chronic obstructive pulmonary disease.

ERJ Open Res 2021 Jul 26;7(3). Epub 2021 Jul 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p<0.001; Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) General Health: p=0.002; SF-36 Physical Health: p<0.001), decreased functional performance (6-min walk distance (6MWD): p<0.001), and severe AECOPD (p=0.01), while polycythaemia was not. Continuous models, however, demonstrated increased morbidity at both ends of the haemoglobin distribution (p<0.01 for mMRC, SGRQ, SF-36 Physical Health, 6MWD, and severe AECOPD). Evaluating interactions, both diffusing capacity and haemoglobin were independently associated with morbidity. We present novel findings that haemoglobin derangements towards either extreme of the observed range are associated with increased morbidity in COPD. Further investigation is necessary to determine whether haemoglobin derangement drives morbidity or merely reflects systemic inflammation, and whether correcting haemoglobin towards the normal range improves morbidity.
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http://dx.doi.org/10.1183/23120541.00068-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311135PMC
July 2021

Blood RNA sequencing shows overlapping gene expression across COPD phenotype domains.

Thorax 2021 Jun 24. Epub 2021 Jun 24.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

Rationale: COPD can be assessed using multidimensional grading systems with components from three domains: pulmonary function tests, symptoms and systemic features. Clinically, measures may be used interchangeably, though it is not known if they share similar pathobiology.

Objective: To use RNA sequencing (RNA-seq) to determine if there is an overlap in the underlying biological mechanisms and consequences driving different components of the multidimensional grading systems.

Methods: Whole blood was collected for RNA-seq from current and former smokers in the Genetic Epidemiology of COPD study. We tested the overlap in gene expression and biological pathways associated with case-control status and quantitative COPD phenotypes within and between the three domains.

Results: In 2647 subjects, there were 3030 genes differentially expressed in any of the three domains or case-control status. There were five genes that overlapped between the three domains and case-control status, including (), () and (), which were associated with longitudinal decline in FEV. The overlap between the three domains was enriched for pathways related to cellular components.

Conclusions: We identified gene sets and pathways that overlap between 12 COPD-related phenotypes and case-control status. There were no pathways represented in the overlap between the three domains and case-control status, but we identified multiple genes that demonstrated a consistent pattern of expression across several of the phenotypes. Patterns of gene expression correlation were generally similar to the correlation of clinical phenotypes in the PFT and symptom domains but not the systemic features.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216401DOI Listing
June 2021

Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment.

Am J Respir Crit Care Med 2021 09;204(6):651-666

Division of Pulmonary and Critical Care Medicine and.

Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects and/or were studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism and ; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin's protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (-0.92%; 95% confidence interval [CI], -1.7% to -0.14%;  = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L;  = 0.01). Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.
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http://dx.doi.org/10.1164/rccm.202012-4510OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521702PMC
September 2021

Lung function trajectories in children with post-prematurity respiratory disease: identifying risk factors for abnormal growth.

Respir Res 2021 May 10;22(1):143. Epub 2021 May 10.

Division of Pulmonary Medicine, Boston Children's Hospital, Boston, MA, USA.

Background: Survivors of prematurity are at risk for abnormal childhood lung function. Few studies have addressed trajectories of lung function and risk factors for abnormal growth in childhood. This study aims to describe changes in lung function in a contemporary cohort of children born preterm followed longitudinally in pulmonary clinic for post-prematurity respiratory disease and to assess maternal and neonatal risk factors associated with decreased lung function trajectories.

Methods: Observational cohort of 164 children born preterm ≤ 32 weeks gestation followed in pulmonary clinic at Boston Children's Hospital with pulmonary function testing. We collected demographics and neonatal history. We used multivariable linear regression to identify the impact of neonatal and maternal risk factors on lung function trajectories in childhood.

Results: We identified 264 studies from 82 subjects with acceptable longitudinal FEV data and 138 studies from 47 subjects with acceptable longitudinal FVC and FEV/FVC data. FEV% predicted and FEV/FVC were reduced compared to childhood norms. Growth in FVC outpaced FEV, resulting in an FEV/FVC that declined over time. In multivariable analyses, longer duration of mechanical ventilation was associated with a lower rate of rise in FEV% predicted and greater decline in FEV/FVC, and postnatal steroid exposure in the NICU was associated with a lower rate of rise in FEV and FVC % predicted. Maternal atopy and asthma were associated with a lower rate of rise in FEV% predicted.

Conclusions: Children with post-prematurity respiratory disease demonstrate worsening obstruction in lung function throughout childhood. Neonatal risk factors including exposure to mechanical ventilation and postnatal steroids, as well as maternal atopy and asthma, were associated with diminished rate of rise in lung function. These results may have implications for lung function trajectories into adulthood.
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http://dx.doi.org/10.1186/s12931-021-01720-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112031PMC
May 2021

Inhaled Medication Use in Smokers With Normal Spirometry.

Respir Care 2021 Apr 9;66(4):652-660. Epub 2021 Feb 9.

Division of Pulmonary, Critical Care and Occupational Medicine, University of Iowa Hospital and Clinics, Iowa City, Iowa.

Background: The objective of our study was to identify variables associated with inhaled medication use in smokers with normal spirometry (GOLD-0) and to examine the association of inhaled medication use with development of exacerbations and obstructive spirometry in the future.

Methods: We performed a retrospective multivariable analysis of GOLD-0 subjects identified in data from the COPDGene study to examine factors associated with medication use. Five categories were identified: (1) no medications, (2) short-acting bronchodilator, (3) long-acting bronchodilator; long-acting muscarinic antagonists and/or long-acting β agonist, (4) inhaled corticosteroids (ICS) with or without long-acting bronchodilator, and (5) dual bronchodilator with ICS. Sensitivity analysis was performed excluding subjects with history of asthma. We also evaluated whether long-acting inhaled medication use was associated with exacerbations and obstructive spirometry at the follow-up visit 5 y after enrollment.

Results: Of 4,303 GOLD-0 subjects within the analysis, 541 of them (12.6%) received inhaled medications. Of these, 259 (6%) were using long-acting inhaled medications and 282 (6.6%) were taking short-acting bronchodilator. Female sex (odds ratio [OR] 1.47, = .003), numerous medical comorbidities, radiographic emphysema (OR 2.22, = .02), chronic bronchitis (OR 1.77, < .001), dyspnea (OR 2.24, < .001), asthma history (OR 15.56, < .001), prior exacerbation (OR 8.45, < .001), and 6-min walk distance (OR 0.9, < .001) were associated with medication use. Minimal changes were noted in a sensitivity analysis. Additionally, inhaled medications were associated with increased total (incidence rate ratio 2.83, < .001) and severe respiratory exacerbations (incidence rate ratio 3.64, < .001) and presence of obstructive spirometry (OR 2.83, = .002) at follow-up.

Conclusions: Respiratory symptoms, history of asthma, and radiographic emphysema were associated with inhaled medication use in smokers with normal spirometry. These individuals were more likely to develop obstructive spirometry, which suggests that health care providers may be able to identify obstructive lung disease prior to meeting the current criteria for COPD.
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http://dx.doi.org/10.4187/respcare.08016DOI Listing
April 2021

Relative contributions of family history and a polygenic risk score on COPD and related outcomes: COPDGene and ECLIPSE studies.

BMJ Open Respir Res 2020 11;7(1)

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

Introduction: Family history is a risk factor for chronic obstructive pulmonary disease (COPD). We previously developed a COPD risk score from genome-wide genetic markers (Polygenic Risk Score, PRS). Whether the PRS and family history provide complementary or redundant information for predicting COPD and related outcomes is unknown.

Methods: We assessed the predictive capacity of family history and PRS on COPD and COPD-related outcomes in non-Hispanic white (NHW) and African American (AA) subjects from COPDGene and ECLIPSE studies. We also performed interaction and mediation analyses.

Results: In COPDGene, family history and PRS were significantly associated with COPD in a single model (P <0.0001; P<0.0001). Similar trends were seen in ECLIPSE. The area under the receiver operator characteristic curve for a model containing family history and PRS was significantly higher than a model with PRS (p=0.00035) in NHWs and a model with family history (p<0.0001) alone in NHWs and AAs. Both family history and PRS were significantly associated with measures of quantitative emphysema and airway thickness. There was a weakly positive interaction between family history and the PRS under the additive, but not multiplicative scale in NHWs (relative excess risk due to interaction=0.48, p=0.04). Mediation analyses found that a significant proportion of the effect of family history on COPD was mediated through PRS in NHWs (16.5%, 95% CI 9.4% to 24.3%), but not AAs.

Conclusion: Family history and the PRS provide complementary information for predicting COPD and related outcomes. Future studies can address the impact of obtaining both measures in clinical practice.
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http://dx.doi.org/10.1136/bmjresp-2020-000755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689586PMC
November 2020

Characterization of a COPD-Associated Functional Splicing Genetic Variant in Human Lung Tissue via Long-Read Sequencing.

medRxiv 2020 Nov 3. Epub 2020 Nov 3.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. Genome-wide association studies (GWAS) have identified over 80 loci that are associated with COPD and emphysema, however for most of these loci the causal variant and gene are unknown. Here, we utilize lung splice quantitative trait loci (sQTL) data from the Genotype-Tissue Expression project (GTEx) and short read sequencing data from the Lung Tissue Research Consortium (LTRC) to characterize a locus in nephronectin ( ) associated with COPD case-control status and lung function. We found that the rs34712979 variant is associated with alternative splice junction use in , specifically for the junction connecting the 2nd and 4th exons (chr4:105898001-105927336) (p=4.02×10 ). This association colocalized with GWAS data for COPD and lung spirometry measures with a posterior probability of 94%, indicating that the same causal genetic variants in underlie the associations with COPD risk, spirometric measures of lung function, and splicing. Investigation of short read sequencing revealed that rs34712979 creates a cryptic splice acceptor site which results in the inclusion of a 3 nucleotide exon extension, coding for a serine residue near the N-terminus of the protein. Using Oxford Nanopore Technologies (ONT) long read sequencing we identified 13 isoforms, 6 of which are predicted to be protein coding. Two of these are full length isoforms which differ only in the 3 nucleotide exon extension whose occurrence differs by genotype. Overall, our data indicate that rs34712979 modulates COPD risk and lung function by creating a novel splice acceptor which results in the inclusion of a 3 nucelotide sequence coding for a serine in the nephronectin protein sequence. Our findings implicate splicing in contributing to COPD risk, and identify a novel serine insertion in the nephronectin protein that warrants further study.
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http://dx.doi.org/10.1101/2020.10.20.20203927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654922PMC
November 2020

Somatotypes trajectories during adulthood and their association with COPD phenotypes.

ERJ Open Res 2020 Jul 14;6(3). Epub 2020 Sep 14.

Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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) while the other 12% a heavier somatotype (estimated BMI between 25 and 27 kg·m). 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 (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 (FEV), , 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.
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http://dx.doi.org/10.1183/23120541.00122-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487345PMC
July 2020

Sex-specific associations with DNA methylation in lung tissue demonstrate smoking interactions.

Epigenetics 2021 Jun 22;16(6):692-703. Epub 2020 Sep 22.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.

Cigarette smoking impacts DNA methylation, but the investigation of sex-specific features of lung tissue DNA methylation in smokers has been limited. Women appear more susceptible to cigarette smoke, and often develop more severe lung disease at an earlier age with less smoke exposure. We aimed to analyse whether there are sex differences in DNA methylation in lung tissue and whether these DNA methylation marks interact with smoking. We collected lung tissue samples from former smokers who underwent lung tissue resection. One hundred thirty samples from white subjects were included for this analysis. Regression models for sex as a predictor of methylation were adjusted for age, presence of COPD, smoking variables and technical batch variables revealed 710 associated sites. 294 sites demonstrated robust sex-specific methylation associations in foetal lung tissue. Pathway analysis identified 6 nominally significant pathways including the mitophagy pathway. Three CpG sites demonstrated a suggested interaction between sex and pack-years of smoking: GPR132, ANKRD44 and C19orf60. All of them were nominally significant in both male- and female-specific models, and the effect estimates were in opposite directions for male and female; GPR132 demonstrated significant association between DNA methylation and gene expression in lung tissue ( < 0.05). Sex-specific associations with DNA methylation in lung tissue are wide-spread and may reveal genes and pathways relevant to sex differences for lung damaging effects of cigarette smoking.
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http://dx.doi.org/10.1080/15592294.2020.1819662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143227PMC
June 2021

Genome-Wide Association Study: Functional Variant rs2076295 Regulates Desmoplakin Expression in Airway Epithelial Cells.

Am J Respir Crit Care Med 2020 11;202(9):1225-1236

Channing Division of Network Medicine and.

Genetic association studies have identified rs2076295 in association with idiopathic pulmonary fibrosis (IPF). We hypothesized that rs2076295 is the functional variant regulating () expression in human bronchial epithelial cells, and regulates extracellular matrix-related gene expression and cell migration, which is relevant to IPF development. To determine whether rs2076295 regulates expression and the function of DSP in airway epithelial cells. Using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 editing (including regional deletion, indel, CRISPR interference, and single-base editing), we modified rs2076295 and measured expression in edited 16HBE14o- and primary airway epithelial cells. Cellular integrity, migration, and genome-wide gene expression changes were examined in 16HBE14o- single colonies with knockout. The expression of and its relevant matrix genes was measured by quantitative PCR and also analyzed in single-cell RNA-sequencing data from control and IPF lungs. is expressed predominantly in bronchial and alveolar epithelial cells, with reduced expression in alveolar epithelial cells in IPF lungs. The deletion of the DNA region-spanning rs2076295 led to reduced expression of , and the edited rs2076295GG 16HBE14o- line has lower expression of than the rs2076295TT lines. Knockout of in 16HBE14o- cells decreased transepithelial resistance but increased cell migration, with increased expression of extracellular matrix-related genes, including and . Silencing of and abolished increased migration in -knockout cells. rs2076295 regulates expression in human airway epithelial cells. The loss of enhances extracellular matrix-related gene expression and promotes cell migration, which may contribute to the pathogenesis of IPF.
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http://dx.doi.org/10.1164/rccm.201910-1958OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605184PMC
November 2020

Clinical Phenotypes of Atopy and Asthma in COPD: A Meta-analysis of SPIROMICS and COPDGene.

Chest 2020 12 23;158(6):2333-2345. Epub 2020 May 23.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: Little is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies.

Research Question: What is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)?

Study Design And Methods: Four hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis.

Results: The prevalence of atopy was 35% and 36% in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50% overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95% CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95% CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95% CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes.

Interpretation: Asthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk.
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http://dx.doi.org/10.1016/j.chest.2020.04.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768932PMC
December 2020

Vitamin D deficiency is associated with respiratory symptoms and airway wall thickening in smokers with and without COPD: a prospective cohort study.

BMC Pulm Med 2020 May 4;20(1):123. Epub 2020 May 4.

Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02115, USA.

Background: Previous studies have established a higher prevalence of vitamin D deficiency in patients with COPD, but the relationship between vitamin D levels and COPD exacerbations remains controversial. In addition, the effect of vitamin D levels on imaging characteristics remains mostly unexplored. Using cross-sectional and longitudinal follow up data from the COPDGene Study, we assessed the association between vitamin D levels on respiratory symptoms, exacerbations, and imaging characteristics. We hypothesized that vitamin D deficiency will be associated with worse respiratory-related outcomes.

Methods: Current and former smokers between ages 45-80 were enrolled the COPDGene Study. Subjects completed questionnaires, spirometry, six-minute walk test, and chest computed tomography scans. A subset of subjects had measurement of serum concentration of 25-hydroxyvitamin D (25(OH)D). Vitamin D deficiency was defined as serum concentration less than 20 ng/mL. Longitudinal follow up was conducted via a web-based or telephone questionnaire.

Results: Vitamin D levels were measured on 1544 current and former smokers, of which 981 subjects had sufficient vitamin D levels and 563 subjects had vitamin D deficiency. Subjects with vitamin D deficiency were younger with increased likelihood of being African American, being current smokers, having a lower percent predicted FEV, and having COPD. Vitamin D deficiency was associated with worse quality of life, increased dyspnea, decreased exercise tolerance, and increased frequency of severe exacerbations. Vitamin D deficiency was also associated with increased segmental airway wall thickness on chest CT scans.

Conclusion: Vitamin D deficiency was associated with increased respiratory symptoms, decreased functional status, increased frequency of severe exacerbations, as well as airway wall thickening on chest CT scans. Further research is needed to determine the potential impact of vitamin D supplementation to improve disease outcomes.
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http://dx.doi.org/10.1186/s12890-020-1148-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199369PMC
May 2020

Heme metabolism genes Downregulated in COPD Cachexia.

Respir Res 2020 May 1;21(1):100. Epub 2020 May 1.

Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.

Introduction: Cachexia contributes to increased mortality and reduced quality of life in Chronic Obstructive Pulmonary Disease (COPD) and may be associated with underlying gene expression changes. Our goal was to identify differential gene expression signatures associated with COPD cachexia in current and former smokers.

Methods: We analyzed whole-blood gene expression data from participants with COPD in a discovery cohort (COPDGene, N = 400) and assessed replication (ECLIPSE, N = 114). To approximate the consensus definition using available criteria, cachexia was defined as weight-loss > 5% in the past 12 months or low body mass index (BMI) (< 20 kg/m) and 1/3 criteria: decreased muscle strength (six-minute walk distance < 350 m), anemia (hemoglobin < 12 g/dl), and low fat-free mass index (FFMI) (< 15 kg/m among women and < 17 kg/m among men) in COPDGene. In ECLIPSE, cachexia was defined as weight-loss > 5% in the past 12 months or low BMI and 3/5 criteria: decreased muscle strength, anorexia, abnormal biochemistry (anemia or high c-reactive protein (> 5 mg/l)), fatigue, and low FFMI. Differential gene expression was assessed between cachectic and non-cachectic subjects, adjusting for age, sex, white blood cell counts, and technical covariates. Gene set enrichment analysis was performed using MSigDB.

Results: The prevalence of COPD cachexia was 13.7% in COPDGene and 7.9% in ECLIPSE. Fourteen genes were differentially downregulated in cachectic versus non-cachectic COPD patients in COPDGene (FDR < 0.05) and ECLIPSE (FDR < 0.05).

Discussion: Several replicated genes regulating heme metabolism were downregulated among participants with COPD cachexia. Impaired heme biosynthesis may contribute to cachexia development through free-iron buildup and oxidative tissue damage.
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http://dx.doi.org/10.1186/s12931-020-01336-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193359PMC
May 2020

Immunoglobulin E as a Biomarker for the Overlap of Atopic Asthma and Chronic Obstructive Pulmonary Disease.

Chronic Obstr Pulm Dis 2020 Jan;7(1):1-12

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.

Asthma-COPD overlap (ACO) is a common clinical syndrome, yet there is no single objective definition. We hypothesized that immunoglobulin E (IgE) measurements could be used to refine the definition of ACO. In baseline plasma samples from 2870 participants in the COPD Genetic Epidemiology (COPDGene®) study, we measured total IgE levels and specific IgE levels to 6 common allergens. Compared to usual chronic obstructive pulmonary disease (COPD), participants with ACO (based on self-report of asthma) had higher total IgE levels (median 67.0 versus 42.2 IU/ml) and more frequently had at least one positive specific IgE (43.5% versus 24.5%). We previously used a strict definition of ACO in participants with COPD, based on self-report of a doctor's diagnosis of asthma before age 40. This strict ACO definition was refined by the presence of atopy, determined by total IgE > 100 IU/ml or at least one positive specific IgE, as was the broader definition of ACO based on self-reported asthma history. Participants with all 3 ACO definitions were younger (mean age 60.0-61.3 years), were more commonly African American (36.8%-44.2%), had a higher exacerbation frequency (1.0-1.2 in the past year), and had more airway wall thickening on quantitative analysis of chest computed tomography (CT) scans. Among participants with ACO, 37%-46% did not have atopy; these individuals had more emphysema on chest CT scan. Based on associations with exacerbations and CT airway disease, IgE did not clearly improve the clinical definition of ACO. However, IgE measurements could be used to subdivide individuals with atopic and non-atopic ACO, who might have different biologic mechanisms and potential treatments.
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http://dx.doi.org/10.15326/jcopdf.7.1.2019.0138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182380PMC
January 2020

DNA Methylation Is Predictive of Mortality in Current and Former Smokers.

Am J Respir Crit Care Med 2020 05;201(9):1099-1109

Channing Division of Network Medicine and.

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 of the human genome that has been associated with both cigarette smoking and mortality. We sought to identify DNA methylation marks in blood that are predictive of mortality in a subset of the COPDGene (Genetic Epidemiology of COPD) study, representing 101 deaths among 667 current and former smokers. We assayed genome-wide DNA methylation in non-Hispanic white smokers with and without chronic obstructive pulmonary disease (COPD) using blood samples from the COPDGene enrollment visit. We tested whether DNA methylation was associated with mortality in models adjusted for COPD status, age, sex, current smoking status, and pack-years of cigarette smoking. Replication was performed in a subset of 231 individuals from the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study. We identified seven CpG sites associated with mortality (false discovery rate < 20%) that replicated in the ECLIPSE cohort ( < 0.05). None of these marks were associated with longitudinal lung function decline in survivors, smoking history, or current smoking status. However, differential methylation of two replicated (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta) sites were associated with lung function at enrollment ( < 0.05). We also observed associations between DNA methylation and gene expression for the sites. This study is the first to identify variable DNA methylation associated with all-cause mortality in smokers with and without COPD. Evaluating predictive epigenomic marks of smokers in peripheral blood may allow for targeted risk stratification and aid in delivery of future tailored therapeutic interventions.
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http://dx.doi.org/10.1164/rccm.201902-0439OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193844PMC
May 2020

Machine Learning Characterization of COPD Subtypes: Insights From the COPDGene Study.

Chest 2020 05 28;157(5):1147-1157. Epub 2019 Dec 28.

Department of Epidemiology, University of Colorado, Denver, Aurora, CO.

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.
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http://dx.doi.org/10.1016/j.chest.2019.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242638PMC
May 2020

Correction to: RNA sequencing identifies novel non-coding RNA and exon-specific effects associated with cigarette smoking.

BMC Med Genomics 2019 11 18;12(1):166. Epub 2019 Nov 18.

Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Ave, Boston, MA, USA.

Following publication of the original article [1], the authors provided an updated accession number in the "Availability of data and materials" section of the declarations.
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http://dx.doi.org/10.1186/s12920-019-0617-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859605PMC
November 2019

COPDGene 2019: Redefining the Diagnosis of Chronic Obstructive Pulmonary Disease.

Chronic Obstr Pulm Dis 2019 Nov;6(5):384-399

Northeastern University, Boston, Massachusetts.

Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality.

Methods: Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined.

Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics.

Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.
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http://dx.doi.org/10.15326/jcopdf.6.5.2019.0149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020846PMC
November 2019

Diffusing Capacity of Carbon Monoxide in Assessment of COPD.

Chest 2019 12 25;156(6):1111-1119. Epub 2019 Jul 25.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD. Electronic address:

Background: Diffusing capacity of the lung for carbon monoxide (Dlco) is inconsistently obtained in patients with COPD, and the added benefit of Dlco testing beyond that of more common tools is unknown.

Objective: The goal of this study was to determine whether lower Dlco is associated with increased COPD morbidity independent of emphysema assessed via spirometry and CT imaging.

Methods: Data for 1,806 participants with COPD from the Genetic Epidemiology of COPD (COPDGene) study 5-year visit were analyzed, including pulmonary function testing, quality of life, symptoms, exercise performance, and exacerbation rates. Dlco percent predicted was primarily analyzed as a continuous variable and additionally categorized into four groups: (1) Dlco and FEV > 50% (reference); (2) only Dlco ≤ 50%; (3) only FEV ≤ 50%; and (4) both ≤ 50% predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV percent predicted among other confounders.

Results: In multivariable analyses, every 10% predicted decrease in Dlco was associated with symptoms and quality of life (COPD Assessment Test, 0.53 [P < .001]; St. George's Respiratory Questionnaire, 1.67 [P < .001]; Medical Outcomes Study Short Form 36 Physical Function, -0.89 [P < .001]), exercise performance (6-min walk distance, -45.35 feet; P < .001), and severe exacerbation rate (rate ratio, 1.14; P < .001). When categorized, severe impairment in Dlco alone, FEV alone, or both Dlco and FEV were associated with significantly worse morbidity compared with the reference group (P < .05 for all outcomes).

Conclusions: Impairment in Dlco was associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk even after accounting for spirometry and CT evidence of emphysema. These findings suggest that Dlco should be considered for inclusion in future multidimensional tools assessing COPD.
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http://dx.doi.org/10.1016/j.chest.2019.06.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242635PMC
December 2019

Identification of an emphysema-associated genetic variant near with regulatory effects in lung fibroblasts.

Elife 2019 07 25;8. Epub 2019 Jul 25.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, United States.

Murine studies have linked TGF-β signaling to emphysema, and human genome-wide association studies (GWAS) studies of lung function and COPD have identified associated regions near genes in the TGF-β superfamily. However, the functional regulatory mechanisms at these loci have not been identified. We performed the largest GWAS of emphysema patterns to date, identifying 10 GWAS loci including an association peak spanning a 200 kb region downstream from . Integrative analysis of publicly available eQTL, DNaseI, and chromatin conformation data identified a putative functional variant, rs1690789, that may regulate expression in human fibroblasts. Using chromatin conformation capture, we confirmed that the region containing rs1690789 contacts the promoter in fibroblasts, and CRISPR/Cas-9 targeted deletion of a ~ 100 bp region containing rs1690789 resulted in decreased expression in primary human lung fibroblasts. These data provide novel mechanistic evidence linking genetic variation affecting the TGF-β pathway to emphysema in humans.
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http://dx.doi.org/10.7554/eLife.42720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693893PMC
July 2019

Analysis of genetically driven alternative splicing identifies FBXO38 as a novel COPD susceptibility gene.

PLoS Genet 2019 07 3;15(7):e1008229. Epub 2019 Jul 3.

Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.

While many disease-associated single nucleotide polymorphisms (SNPs) are associated with gene expression (expression quantitative trait loci, eQTLs), a large proportion of complex disease genome-wide association study (GWAS) variants are of unknown function. Some of these SNPs may contribute to disease by regulating gene splicing. Here, we investigate whether SNPs that are associated with alternative splicing (splice QTL or sQTL) can identify novel functions for existing GWAS variants or suggest new associated variants in chronic obstructive pulmonary disease (COPD). RNA sequencing was performed on whole blood from 376 subjects from the COPDGene Study. Using linear models, we identified 561,060 unique sQTL SNPs associated with 30,333 splice sites corresponding to 6,419 unique genes. Similarly, 708,928 unique eQTL SNPs involving 15,913 genes were detected at 10% FDR. While there is overlap between sQTLs and eQTLs, 55.3% of sQTLs are not eQTLs. Co-localization analysis revealed that 7 out of 21 loci associated with COPD (p<1x10-6) in a published GWAS have at least one shared causal variant between the GWAS and sQTL studies. Among the genes identified to have splice sites associated with top GWAS SNPs was FBXO38, in which a novel exon was discovered to be protective against COPD. Importantly, the sQTL in this locus was validated by qPCR in both blood and lung tissue, demonstrating that splice variants relevant to lung tissue can be identified in blood. Other identified genes included CDK11A and SULT1A2. Overall, these data indicate that analysis of alternative splicing can provide novel insights into disease mechanisms. In particular, we demonstrated that SNPs in a known COPD GWAS locus on chromosome 5q32 influence alternative splicing in the gene FBXO38.
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http://dx.doi.org/10.1371/journal.pgen.1008229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634423PMC
July 2019

Clinical Epidemiology of COPD: Insights From 10 Years of the COPDGene Study.

Chest 2019 08 30;156(2):228-238. Epub 2019 May 30.

Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO. Electronic address:

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.
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http://dx.doi.org/10.1016/j.chest.2019.04.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198872PMC
August 2019
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