ABSTRACT
Most genetic variants identified through genome-wide association studies (GWAS) are suspected to be regulatory in nature, but only a small fraction colocalize with expression quantitative trait loci (eQTLs, variants associated with expression of a gene). Therefore, it is hypothesized but largely untested that integration of disease GWAS with context-specific eQTLs will reveal the underlying genes driving disease associations. We used colocalization and transcriptomic analyses to identify shared genetic variants and likely causal genes associated with critically ill COVID-19 and idiopathic pulmonary fibrosis. We first identified five genome-wide significant variants associated with both diseases. Four of the variants did not demonstrate clear colocalization between GWAS and healthy lung eQTL signals. Instead, two of the four variants colocalized only in cell-type and disease-specific eQTL datasets. These analyses pointed to higher ATP11A expression from the C allele of rs12585036, in monocytes and in lung tissue from primarily smokers, which increased risk of IPF and decreased risk of critically ill COVID-19. We also found lower DPP9 expression (and higher methylation at a specific CpG) from the G allele of rs12610495, acting in fibroblasts and in IPF lungs, and increased risk of IPF and critically ill COVID-19. We further found differential expression of the identified causal genes in diseased lungs when compared to non-diseased lungs, specifically in epithelial and immune cell types. These findings highlight the power of integrating GWAS, context-specific eQTLs, and transcriptomics of diseased tissue to harness human genetic variation to identify causal genes and where they function during multiple diseases.
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Rationale: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. Objectives: Define high-risk COPD subtypes using both genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics. Methods: We defined high-risk groups based on PRS and TRS quantiles by maximizing differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups. Measurements and Main Results: We examined two high-risk omics-defined groups in non-overlapping test sets (n=1,133 NHW COPDGene, n=299 African American (AA) COPDGene, n=468 ECLIPSE). We defined "High activity" (low PRS/high TRS) and "severe risk" (high PRS/high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signaling processes compared to a low-risk (low PRS, low TRS) reference subgroup. "High activity" but not "severe risk" participants had greater prospective FEV 1 decline (COPDGene: -51 mL/year; ECLIPSE: - 40 mL/year) and their proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors. Conclusions: Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection.
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BACKGROUND: DNA methylation may be a link between HIV, aging, and the increased risk of lung comorbidities. We investigated whether bronchoalveolar lavage (BAL) cells of people living with HIV (PLWH) demonstrate epigenetic disruptions and advanced epigenetic aging. METHODS: BAL cell DNA methylation from 25 PLWH and 16 HIV-uninfected individuals were tested for differential methylation of Alu and LINE-1 sites, markers of aging. We used a weighted gene correlation network analysis to identify HIV- and age-associated co-methylation networks. We tested the effect of HIV on DNA methylation using a robust linear model (false discovery rate < 0.10). RESULTS: The BAL cells of PLWH were marked by global hypomethylation in both Alu and LINE-1 elements. Six co-methylated CpG networks were identified that were significantly associated with age; of these, the red module was significantly differentially methylated in PLWH and enriched pathways (e.g., Ras signaling and T-cell receptors). We identified 6428 CpG sites associated with HIV. CONCLUSIONS: We have shown here for the first time that alterations in the DNA methylation of BAL cells in the lung with HIV show a pattern of advanced aging. This study strongly supports that HIV may contribute to an increased the risk of lung comorbidities through the epigenetics of aging.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Tomography, X-Ray Computed , Humans , Pulmonary Disease, Chronic Obstructive/diagnostic imaging , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/physiopathology , Tomography, X-Ray Computed/methods , Male , Chronic Disease , Female , Middle Aged , Aged , Multiple Chronic ConditionsABSTRACT
Hyperpolarized 129Xe gas MRI is an emerging technique to evaluate and measure regional lung function including pulmonary gas distribution and gas exchange. Chest computed tomography (CT) still remains the clinical gold standard for imaging of the lungs, though, in part due to the rapid CT protocols that acquire high-resolution images in seconds and the widespread availability of CT scanners. Quantitative approaches have enabled the extraction of structural lung parenchymal, airway and vascular measurements from chest CT that have been evaluated in many clinical research studies. Together, CT and 129Xe MRI provide complementary information that can be used to evaluate regional lung structure and function, resulting in new insights into lung health and disease. 129Xe MR-CT image registration can be performed to measure regional lung structure-function to better understand lung disease pathophysiology, and to perform image-guided pulmonary interventions. Here, a method for 129Xe MRI-CT registration is outlined to support implementation in research or clinical settings. Registration methods and applications that have been employed to date in the literature are also summarized, and suggestions are provided for future directions that may further overcome technical challenges related to 129Xe MR-CT image registration and facilitate broader implementation of regional lung structure-function evaluation.
Subject(s)
Lung , Magnetic Resonance Imaging , Tomography, X-Ray Computed , Xenon Isotopes , Magnetic Resonance Imaging/methods , Xenon Isotopes/chemistry , Lung/diagnostic imaging , Humans , Tomography, X-Ray Computed/methods , Multimodal Imaging/methods , AnimalsSubject(s)
Epigenesis, Genetic , Marijuana Smoking , Humans , Male , Female , Marijuana Smoking/adverse effects , Middle Aged , Adult , DNA Methylation , AgedABSTRACT
INTRODUCTION: Chronic obstructive pulmonary disease (COPD) accounts for 545 million people living with chronic respiratory disorders and is the third leading cause of morbidity and mortality around the world. COPD is a progressive disease, characterized by episodes of acute worsening of symptoms such as cough, dyspnea, and sputum production. AREAS COVERED: Airway inflammation is a prominent feature of COPD. Chronic airway inflammation results in airway structural remodeling and emphysema. Persistent airway inflammation is a treatable trait of COPD and plays a significant role in disease development and progression. In this review, the authors summarize the current and emerging biomarkers that reveal the heterogeneity of airway inflammation subtypes, clinical outcomes, and therapeutic response in COPD. EXPERT OPINION: Airway inflammation can be broadly categorized as eosinophilic (type 2 inflammation) and non-eosinophilic (non-type 2 inflammation) in COPD. Currently, blood eosinophil counts are incorporated in clinical practice guidelines to identify COPD patients who are at a higher risk of exacerbations and lung function decline, and who are likely to respond to inhaled corticosteroids. As new therapeutics are being developed for the chronic management of COPD, it is essential to identify biomarkers that will predict treatment response.
Subject(s)
Biomarkers , Pulmonary Disease, Chronic Obstructive , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/metabolism , Pulmonary Disease, Chronic Obstructive/blood , Humans , Biomarkers/blood , Eosinophils/metabolism , Inflammation/metabolism , PrognosisABSTRACT
Mucus forms the first defense line of human lungs, and as such hampers the efficient delivery of therapeutics to the underlying epithelium. This holds particularly true for genetic cargo such as CRISPR-based gene editing tools which cannot readily surmount the mucosal barrier. While lipid nanoparticles (LNPs) emerge as versatile non-viral gene delivery systems that can help overcome the delivery challenge, many knowledge gaps remain, especially for diseased states such as cystic fibrosis (CF). This study provides fundamental insights into Cas9 mRNA or ribonucleoprotein-loaded LNP-mucus interactions in healthy and diseased states by assessing the impact of the genetic cargo, mucin sialylation, mucin concentration, ionic strength, pH, and polyethylene glycol (PEG) concentration and nature on LNP diffusivity leveraging experimental approaches and Brownian dynamics (BD) simulations. Taken together, this study identifies key mucus and LNP characteristics that are critical to enabling a rational LNP design for transmucosal delivery.
Subject(s)
Cystic Fibrosis , Mucus , Nanoparticles , Polyethylene Glycols , Cystic Fibrosis/metabolism , Humans , Nanoparticles/chemistry , Mucus/metabolism , Polyethylene Glycols/chemistry , Lipids/chemistry , Mucins/metabolism , Mucins/chemistry , Gene Transfer Techniques , LiposomesABSTRACT
Globally, nearly 400 million persons have COPD, and COPD is one of the leading causes of hospitalisation and mortality across the world. While it has been long-recognised that COPD is an inflammatory lung disease, dissimilar to asthma, type 2 inflammation was thought to play a minor role. However, recent studies suggest that in approximately one third of patients with COPD, type 2 inflammation may be an important driver of disease and a potential therapeutic target. Importantly, the immune cells and molecules involved in COPD-related type 2 immunity may be significantly different from those observed in severe asthma. Here, we identify the important molecules and effector immune cells involved in type 2 airway inflammation in COPD, discuss the recent therapeutic trial results of biologicals that have targeted these pathways and explore the future of therapeutic development of type 2 immune modulators in COPD.
Subject(s)
Inflammation , Pulmonary Disease, Chronic Obstructive , Pulmonary Disease, Chronic Obstructive/immunology , Humans , Inflammation/immunology , Th2 Cells/immunology , Asthma/immunologyABSTRACT
BACKGROUND: Long COVID impacts â¼10% of people diagnosed with COVID-19, yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID, therefore we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes. METHODS: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129XeMRI â¼14-months post-acute infection across three centres. Long COVID was defined as persistent dyspnea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully-recovered. 129XeMRI ventilation defect percent (VDP) and membrane (Mem)/Gas, red blood cell (RBC)/Mem and RBC/Gas ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction. RESULTS: We evaluated 135 participants across three centres: 28 COVID-negative (40±16yrs), 34 fully-recovered (42±14yrs) and 73 long COVID (49±13yrs). RBC/Mem (p=0.03) and FEV1 (p=0.04) were different between long- and COVID-negative; FEV1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster1 was the youngest with normal MRI and mild gas-trapping; Cluster2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster3 had mildly increased Mem/Gas with normal PFTs; and Cluster4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern. CONCLUSION: We identified four 129XeMRI long COVID phenotypes with distinct characteristics. 129XeMRI can dissect pathophysiologic heterogeneity of long COVID to enable personalised patient care.
ABSTRACT
Chronic obstructive pulmonary disease (COPD) is caused by smoking, but only a small proportion of smokers have disease severe enough to develop COPD. COPD is not always progressive. The question then arises as to what explains the different trajectories of COPD. The role of autoimmunity and regulatory T (Treg) cells in the pathogenesis of COPD is increasingly being recognized. Nine published studies on Treg cells in the lung tissue or bronchoalveolar lavage fluid have shown that smokers with COPD have fewer Treg cells than smokers without COPD or nonsmokers. Three studies showed a positive correlation between Treg cell count and FEV1%, suggesting an important role for Treg cells in COPD progression. Treg cells can regulate immunological responses via the granzyme B (GzmB) pathway. Immunohistochemical staining for GzmB in surgically resected lungs with centrilobular emphysema showed that the relationship between the amount of GzmB+ cells and FEV1% was comparable to that between Treg cell count and FEV1% in the COPD lung, suggesting that GzmB could be a functional marker for Treg cells. The volume fraction of GzmB+ cells in the small airways, the number of alveolar GzmB+ cells, and GzmB expression measured by enzyme-linked immunosorbent assay in the lung tissue of smokers were significantly correlated with FEV1%. These results suggest that the GzmB content in lung tissue may determine the progression of COPD by acting as an effector molecule to control inflammatory process. Interventions to augment GzmB-producing immunosuppressive cells in the early stages of COPD could help prevent or delay COPD progression.
Subject(s)
Pulmonary Disease, Chronic Obstructive , Pulmonary Emphysema , Humans , Granzymes/metabolism , Lung , Pulmonary Emphysema/complications , Smoking/adverse effectsABSTRACT
Chronic obstructive pulmonary disease (COPD) affects close to 400 million people worldwide and is the 3rd leading cause of mortality. It is a heterogeneous disorder with multiple endophenotypes, each driven by specific molecular networks and processes. Therapeutic discovery in COPD has lagged behind other disease areas owing to a lack of understanding of its pathobiology and scarcity of biomarkers to guide therapies. Single cell RNA sequencing (scRNA-seq) is a powerful new tool to identify important cellular and molecular networks that play a crucial role in disease pathogenesis. This paper provides an overview of the scRNA-seq technology and its application in COPD and the lessons learned to date from scRNA-seq experiments in COPD.
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OBJECTIVE: To examine the risk of adverse cardiovascular (CV) events following an exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: This retrospective cohort study identified patients with COPD using administrative data from Alberta, Canada from 2014 to 2019. Exposure periods were 12 months following moderate or severe exacerbations; the reference period was time preceding a first exacerbation. The primary outcome was the composite of all-cause death or a first hospitalisation for acute coronary syndrome, heart failure (HF), arrhythmia or cerebral ischaemia. Time-dependent Cox regression models estimated covariate-adjusted risks associated with six exposure subperiods following exacerbation. RESULTS: Among 1 42 787 patients (mean age 68.1 years and 51.7% men) 61 981 (43.4%) experienced at least one exacerbation and 34 068 (23.9%) died during median follow-up of 64 months. The primary outcome occurred in 43 564 (30.5%) patients with an incidence rate prior to exacerbation of 5.43 (95% CI 5.36 to 5.50) per 100 person-years. This increased to 95.61 per 100 person-years in the 1-7 days postexacerbation (adjusted HR 15.86, 95% CI 15.17 to 16.58) and remained increased for up to 1 year. The risk of both the composite and individual CV events was increased following either a moderate or a severe exacerbation, though greater and more prolonged following severe exacerbation. The highest magnitude of increased risk was observed for HF decompensation (1-7 days, HR 72.34, 95% CI 64.43 to 81.22). CONCLUSION: Moderate and severe COPD exacerbations are independent risk factors for adverse CV events, especially HF decompensation. The impact of optimising COPD management on CV outcomes should be evaluated.
Subject(s)
Cardiovascular Diseases , Disease Progression , Pulmonary Disease, Chronic Obstructive , Humans , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/mortality , Male , Female , Aged , Retrospective Studies , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/etiology , Cardiovascular Diseases/mortality , Alberta/epidemiology , Middle Aged , Risk Assessment/methods , Time Factors , Incidence , Risk Factors , Cause of Death , Hospitalization/statistics & numerical dataABSTRACT
PURPOSE OF REVIEW: Spirometry is a validated tool in the diagnosis of obstructive airways disease. However, it may be insufficiently sensitive in detecting airflow limitation in the small airways. This review highlights common clinical scenarios wherein airflow limitation may be missed or overlooked. RECENT FINDINGS: This article covers recent literature on the interpretation of lung function test, focusing on detection of mild obstructive airways disease. It also sheds light on the contextual difficulties of defining mild airflow limitation on spirometry. SUMMARY: We highlight the consensus definition of mild obstructive airways disease and emphasize that this definition does not necessarily mean mild in certain disease-specific contexts. Several spirometric findings outside of a reduced forced expiratory volume in one second/forced vital capacity ratio should raise suspicion of mild obstruction.
Subject(s)
Airway Obstruction , Lung Diseases, Obstructive , Humans , Spirometry , Forced Expiratory VolumeABSTRACT
Rationale: Emphysema is a chronic obstructive pulmonary disease phenotype with important prognostic implications. Identifying blood-based biomarkers of emphysema will facilitate early diagnosis and development of targeted therapies. Objectives: To discover blood omics biomarkers for chest computed tomography-quantified emphysema and develop predictive biomarker panels. Methods: Emphysema blood biomarker discovery was performed using differential gene expression, alternative splicing, and protein association analyses in a training sample of 2,370 COPDGene participants with available blood RNA sequencing, plasma proteomics, and clinical data. Internal validation was conducted in a COPDGene testing sample (n = 1,016), and external validation was done in the ECLIPSE study (n = 526). Because low body mass index (BMI) and emphysema often co-occur, we performed a mediation analysis to quantify the effect of BMI on gene and protein associations with emphysema. Elastic net models with bootstrapping were also developed in the training sample sequentially using clinical, blood cell proportions, RNA-sequencing, and proteomic biomarkers to predict quantitative emphysema. Model accuracy was assessed by the area under the receiver operating characteristic curves for subjects stratified into tertiles of emphysema severity. Measurements and Main Results: Totals of 3,829 genes, 942 isoforms, 260 exons, and 714 proteins were significantly associated with emphysema (false discovery rate, 5%) and yielded 11 biological pathways. Seventy-four percent of these genes and 62% of these proteins showed mediation by BMI. Our prediction models demonstrated reasonable predictive performance in both COPDGene and ECLIPSE. The highest-performing model used clinical, blood cell, and protein data (area under the receiver operating characteristic curve in COPDGene testing, 0.90; 95% confidence interval, 0.85-0.90). Conclusions: Blood transcriptome and proteome-wide analyses revealed key biological pathways of emphysema and enhanced the prediction of emphysema.
Subject(s)
Emphysema , Pulmonary Disease, Chronic Obstructive , Pulmonary Emphysema , Humans , Transcriptome , Proteomics , Pulmonary Emphysema/genetics , Pulmonary Emphysema/complications , Biomarkers , Gene Expression ProfilingABSTRACT
Many patients seen by cardiologists suffer chronic obstructive pulmonary disease (COPD) in addition to their primary cardiovascular problem. Yet, quite often COPD has not been diagnosed and, consequently, patients have not been treated of their pulmonary disease. Recognizing and treating COPD in patients with CVDs is important because optimal treatment of the COPD carries important benefits on cardiovascular outcomes. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) publishes an annual report that serves as a clinical guideline for the diagnosis and management of COPD around the world and has very recently released the 2023 annual report. Here, we provide a summary of the GOLD 2023 recommendations that highlights those aspects of more interest for practicing cardiologists dealing with patients with CVD who may suffer COPD.