The papers listed here were publication spotlights to highlight important scientific advancements published by members of the ATS Section of Genetics and Genomics. As these papers include major advancements in the field, this page will be used to archive each featured publication to allow easy access to this body of literature.
Proteomic Biomarkers of Survival in Idiopathic Pulmonary Fibrosis
Authors: Justin M. Oldham, Yong Huang, Swaraj Bose, Shwu-Fan Ma, John S. Kim, Alexandra Schwab, Christopher Ting, Kaniz Mou, Cathryn T. Lee, Ayodeji Adegunsoye, Sahand Ghodrati, Janelle Vu Pugashetti, Nazanin Nazemi, Mary E. Strek, Angela L. Linderholm, Ching-Hsien Chen, Susan Murray, Rachel L. Zemans, Kevin R. Flaherty, Fernando J. Martinez, and Imre Noth
The study aimed to identify and validate circulating protein biomarkers for predicting survival in idiopathic pulmonary fibrosis (IPF) patients. Using high-throughput proteomic data from plasma samples, the authors identified 231 proteins associated with three-year transplant-free survival (TFS) in a discovery cohort, of which 140 were validated in a separate cohort. Key biomarkers included latent-transforming growth factor β-binding protein 2, collagen α-1(XXIV) chain, and keratin 19. A proteomic signature derived from these proteins outperformed clinical prediction models, providing new insights into IPF progression and potential therapeutic targets.
17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma
Authors:
In this study, Jakwerth and colleagues investigate the heightened viral susceptibility linked to childhood-onset asthma through the 17q21 locus, the strongest and most replicable genetic risk factor. Analyzing nasal brush samples from 261 children, the authors found that the 17q21 risk allele prompts elevated mucosal GSDMB expression, correlating with a proinflammatory, cell-lytic immune response. Notably, this response is associated with compromised airway immunocompetence and reduced levels of IFN type 1 and type 3. These findings suggest that targeting GSDMB-related airway cell death and mucosal IFN signatures could offer new avenues for interventions in respiratory viral infections among carriers of the 17q21 risk allele.
Investigating Associations of Omega-3 Fatty Acids, Lung Function Decline, and Airway Obstruction
Authors: Bonnie K Patchen 1, Pallavi Balte 2, Traci M Bartz 3, R Graham Barr 2, Myriam Fornage 4, Mariaelisa Graff 5, David R Jacobs Jr 6, Ravi Kalhan 7, Rozenn N Lemaitre 3, George O'Connor 8, Bruce Psaty 3, Jungkyun Seo 5, Michael Y Tsai 9, Alexis C Wood 10, Hanfei Xu 11, Jingwen Zhang 11, Sina A Gharib 12, Ani Manichaikul 13, Kari North 4, Lyn M Steffen 5, Josée Dupuis 10 14, Elizabeth Oelsner 2, Dana B Hancock 15, Patricia A Cassano 1 16
Inflammation is associated with lung function decline as measured by spirometry and Omega-3 fatty acids have anti-inflammatory effects. Whether higher levels of omega-3 fatty acids are protective of lung function decline was unknown. In this study, Patchen and colleagues examined the association of omega-3 fatty acid levels with FEV1 and FVC decline in the NHLBI pooled cohorts using linear mixed effects models and repeated spirometry measures. They then leveraged publically-available genome-wide association study (GWAS) data to perform a two-sample Mendelian randomization study using genetic variants to predict omega-3 fatty acid levels. Both analyses provide evidence of a protective effect of higher omega-3 fatty acid levels, especially docosahexaenoic acid, on lung function decline.
Authors:Yuzhuo Wang, Yue Ding, Su Liu, Cheng Wang, Erbao Zhang, Congcong Chen, Meng Zhu, Jing Zhang, Chen Zhu, Mengmeng Ji, Juncheng Dai, Guangfu Jin, Zhibin Hu, Hongbing Shen, Hongxia Ma
In this article, the authors performed a comprehensive splice quantitative trait loci (sQTL) analysis utilizing human lung tissue. They integrated their results with genome-wide association study (GWAS) data and performed a splice-transcriptome-wide association study followed by functional annotation to identify a splice variant associated with reduced non-small cell lung cancer (NSCLC) risk. They validated that this finding by demonstrating that the genetic variant promotes FARP1 exon 20 skipping and decreased expression of the FARP1-011 transcript. This study shows the molecular mechanisms by which splice variants can affect NSCLC risk.
Authors: Mahmoud I. Abdel-Aziz, Jonathan Thorsen, Simone Hashimoto, Susanne J. H. Vijverberg Anne H. Neerincx, Paul Brinkman, Wim van Aalderen, Jakob Stokholm, Morten Arendt Rasmussen, Michael Roggenbuck-Wedemeyer, Nadja H. Vissing, Martin Steen Mortensen, Asker Daniel Brejnrod, Louise J. Fleming, Clare S. Murray, Stephen J. Fowler, Urs Frey, Andrew Bush, Florian Singer, Gunilla Hedlin, Björn Nordlund, Dominick E. Shaw, Kian Fan Chung, Ian M. Adcock, Ratko Djukanovic, Charles Auffray, Aruna T. Bansal, Ana R. Sousa, Scott S. Wagers, Bo Lund Chawes, Klaus Bønnelykke, Søren Johannes Sørensen, Aletta D. Kraneveld, Peter J. Sterk, Graham Roberts, Hans Bisgaard, and Anke H. Maitland-van der Zee; on behalf of the U-BIOPRED Study Group
In this study based in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort, 241 children with pediatric wheezing or school -age asthma were clustered based on their oropharyngeal microbiota profiles. Children were characterized using 16S ribosomal RNA gene sequencing, and unsupervised hierarchical clustering was performed on the Bray-Curtis β-diversity, revealing four taxa-driven clusters dominated by Streptococcus, Veillonella, Rothia, and Haemophilus. The clusters showed significant differences in atopic dermatitis, grass pollen sensitization, FEV1% predicted after salbutamol, and annual asthma exacerbation frequency during follow-up. The Veillonella cluster was the most allergic and included the highest percentage of children with two or more exacerbations per year during follow-up. The findings suggest further exploration of the oropharyngeal microbiota may lead to novel pathophysiologic insights and potentially new treatment approaches.
Blood Gene Expression and Immune Cell Subtypes Associated with COPD Exacerbations
Authors: Yi-Hui Zhou, Paul J Gallins, Rhonda G Pace, Hong Dang, Melis A Aksit, Elizabeth E Blue, Kati J Buckingham, Joseph M Collaco, Anna V Faino, William W Gordon, Kurt N Hetrick, Hua Ling, Weifang Liu, Frankline M Onchiri, Kymberleigh Pagel, Elizabeth W Pugh, Karen S Raraigh, Margaret Rosenfeld, Quan Sun, Jia Wen, Yun Li, Harriet Corvol, Lisa J Strug, Michael J Bamshad, Scott M Blackman, Garry R Cutting, Ronald L Gibson, Wanda K O'Neal, Fred A Wright, Michael R Knowles
Description: Cystic fibrosis is associated with significant mortality and morbidity, however the severity of lung disease in individuals with cystic fibrosis can vary substantially. Identifying genetic modifiers of severity can help to better understand prognosis and to guide the development of novel therapeutics. In this study, whole genome sequencing (WGS) data on 4,248 unique individuals with Cystic Fibrosis, pancreatic insufficiency and lung function measures were combined with imputed genotypes from an additional 3,592 PI patients from the US, Canada, and France to identify associations between single nucleotide polymorphisms and the quantitative Kulich Normal Residual Mortality Adjusted (KNoRMA) lung disease severity phenotype. Pathway analyses identified novel associations with genes that have key roles in organ development, and which may relate to dysanapsis and/or variability in lung repair among individuals with cystic fibrosis. These results confirmed and extended previous GWAS findings and the WGS data provide finely mapped genetic information to support mechanistic studies.
Nasal DNA methylation at three CpG sites predicts childhood allergic disease
Authors: Merlijn van Breugel, Cancan Qi, Zhongli Xu, Casper-Emil T. Pedersen, Ilya Petoukhov, Judith M. Vonk, Ulrike Gehring, Marijn Berg, Marnix Bügel, Orestes A. Carpaij, Erick Forno, Andréanne Morin, Anders U. Eliasen, Yale Jiang, Maarten van den Berge, Martijn C. Nawijn, Yang Li, Wei Chen, Louis J. Bont, Klaus Bønnelykke, Juan C. Celedón, Gerard H. Koppelman & Cheng-Jian Xu
Description: Asthma, rhinitis, and eczema, are among the most prevalent allergic diseases worldwide, with strong genetic and epigenetic contributions. In this study, the authors use supervised machine learning on integrated multi-omics data to predict childhood allergy. For this, data on environmental and genetic factors, as well as blood and nasal DNA methylation from 348 subjects aged 16-years from the Dutch PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort was interrogated.
The study showed that the majority of predictive power could be attributed to nasal DNA methylation, which heavily outperformed genetic risk factors. The authors assessed a wide range of machine learning models and selected Elastic Net for its accuracy, low overfit and interpretability. Using strict feature selection, a parsimonious allergy prediction model was created that only uses three nasal CpG sites. This model achieved a ROC AUC of 0.86 in the discovery PIAMA cohort and 0.82 in a Puerto Rican replication cohort of similar age. Lower performance was observed in two younger Dutch (MAKI) and Danish (COPSAC) cohorts, both at age 6 years. This could be explained by the differing and age dependent methylation levels. The DNA methylation levels of the model’s three CpG sites could differentiate between symptomatic and asymptomatic allergic disease, and also provide information on allergic disease multimorbidity. The identified sites were further analysed using (single-cell) RNA-sequencing data, showing that they reflected the influx of T cells and macrophages that contribute to allergic inflammation.
This research provides novel insights into the strong prediction power of nasal DNA methylation and its potential as non-invasive biomarkers that could, after further validation, be used in an epigenetic diagnostic test for childhood allergy in clinical practice.
Authors: David Scieszka, Stephanie D Byrum, Samuel G Mackintosh, Matthew Madison, John Knight, Matthew J Campen, Farrah Kheradmand
Description: Electronic cigarettes (e-cigs) form an important component of smoking cessation, however their long-term health effects remain uncertain. In this study mice were exposed to filtered air, e-cig vehicle (PGVG), PGVC plus nicotine and cigarette smoke for four months. Proteomics was conducted on the lung bronchoalveolar lavage (BAL) samples and findings were compared to published fibrosis and COPD airway lavage proteomic biomarkers. Overall, the results demonstrated that the exposure conditions of PGVG and PGVG plus Nicotine have differential effects on BAL protein expression after subchronic exposure. PGVG plus Nicotine showed a large number of overlapping biomarkers with smoke exposure confirming the similarities between these exposure conditions. PGVG plus Nicotine also demonstrated a strong overlap with the curated IPF and COPD published biomarkers and these protiens may be indicative of premature lung aging and vulnerability to deleterious chronic outcomes.
Authors: Robert F. J. Kullberg, Justin de Brabander, Leonoor S. Boers, Jason J. Biemond, Esther J. Nossent, Leo M. A. Heunks, Alexander P. J. Vlaar, Peter I. Bonta, Tom van der Poll, JanWillem Duitman, Lieuwe D. J. Bos, and W. Joost Wiersinga; on behalf of the ArtDECO Consortium and the Amsterdam UMC COVID-19 Biobank Study Group
Description:The majority of patients with COVID-19 admitted to the ICU fulfill the criteria for acute respiratory distress syndrome (ARDS). This study aims to determine whether dysbiosis of the lung microbiome may contribute to nonresolving ARDS and increased mortality in such patients. In 114 mechanically ventilated patients with COVID-19 and ARDS, lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. It was observed that patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42-0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42-0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). The bacterial and fungal burden in BAL fluid were correlated with alveolar proinflammatory cytokines such as TNF-a and IL-1b, and lung microbiota community composition was associated with successful extubation. These findings confirm the importance of the lung microbiome in ARDS and COVID-19 and highlight the significance of the—often overlooked—pulmonary fungal burden in critically ill patients.
Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis.
Authors: Luke M Kraven, Adam R Taylor, Philip L Molyneaux, Toby M Maher, John E McDonough, Marco Mura, Ivana V Yang, David A Schwartz, Yong Huang, Imre Noth, Shwu Fan Ma, Astrid J Yeo, William A Fahy, R Gisli Jenkins, Louise V Wain
Description: The clinical course of idiopathic pulmonary fibrosis (IPF) is highly heterogeneous. The identification of IPF endotypes (subtypes defined by a particular pathophysiological mechanism) could help improve the understanding of this complex and ultimately fatal condition and tailor endotype-specific precision management and treatment strategies. In this study, three publicly available blood gene expression datasets including 220 IPF cases were used to derive three distinct clusters of patients with IPF. These clusters, or endotypes, demonstrated significant clinical differences in lung function (p=0.009) and mortality (p=0.009). Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in driving these differences. The authors further developed a 13-gene cluster classifier that was able to predict mortality in two validation cohorts of patients with IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10-5). These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. This study represents the largest unsupervised clustering analysis of available transcriptomic datasets to date, and it unique in its ability to independently validate the resulting endotypes.
This study therefore aimed to generate an in vivo model of SARS-CoV-2 infection based on standard laboratory mice, for testing these new therapeutics. The authors found that a single intranasal dose of rAAV9 or rSIV.F/HN vectors expressing anti-SARS-CoV-2 mAbs significantly reduced SARS-CoV-2 mimic infection in the lower respiratory tract of hACE2-expressing mice. If translated to humans, the VIP approach could potentially offer a highly effective, long-term protection against COVID-19 for highly vulnerable populations; especially immune-deficient/senescent individuals, who fail to respond to conventional SARS-CoV-2 vaccines. The in vivo expression of multiple anti-SARS-CoV-2 mAbs could enhance protection and prevent rapid mutational escape.
Authors: Priyadarshini Kachroo, Isobel D. Stewart, Rachel S. Kelly, Meryl Stav, Kevin Mendez, Amber Dahlin, Djøra I. Soeteman, Su H. Chu, Mengna Huang, Margaret Cote, Hanna M. Knilhtilä, Kathleen Lee-Sarwar, Michael McGeachie, Alberta Wang, Ann Chen Wu, Yamini Virkud, Pei Zhang, Nicholas J. Wareham, Elizabeth W. Karlson, Craig E. Wheelock, Clary Clish, Scott T. Weiss, Claudia Langenberg & Jessica A. Lasky-Su
Description: In the largest metabolomic study of asthma to date, comprising 14,000 individuals from four independent studies, the authors identified and independently replicated 17 steroid metabolites that were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. The results suggest that ICS dosage should be optimized to minimize adrenal suppression while maintaining its established benefits in asthma management.
Author: Rachel S Kelly, Kevin M Mendez, Mengna Huang, Brian D Hobbs, Clary B Clish, Robert Gerszten, Michael H Cho, Craig E Wheelock, Michael J McGeachie, Su H Chu, Juan C Celedón, Scott T Weiss, Jessica Lasky-Su, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Description:There is substantial heterogeneity in the etiology, pathology and manifestation of asthma that is not sufficiently captured by existing treatment guidelines leading to suboptimal management strategies in certain subgroups. Treatments and management strategies based on underlying pathobiological mechanisms may be more effective in terms of improved outcomes and optimized use of health-care resources. Metabolomics reflects genetics, environmental factors, and their interactions, and as the ‘ome closest to phenotype provides insight into the physiological state of an individual, it is theefore particularly well suited to the derivation of disease ‘endotypes' (ie. subtypes based on mechanism). In the Genetics of Asthma in Costa Rica Study untargeted metabolomic profiling, Similarity Network Fusion and spectral clustering was used to derive five metabo-endotypes of asthma, and individuals in these distinct metabo-endotypes were found to differ in asthma-relevant phenotypes, including pre-bronchodilator (p-ANOVA=8.3x10-5) and post-bronchodilator (p-ANOVA=1.8x10-5) forced expiratory volume/forced vital capacity (FEV1/FVC). These metabo-endotypes were then recapitulated in an independent cohort of asthmatics; and the clinical differences between the metabo-endotypes validated. Cholesterol esters, trigylcerides and fatty acids were found to be among the most important drivers of metabo-endotype membership, suggesting dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. These metabo-endotypes provide strong candidates for more precise asthma management strategies while informing on underlying mechanisms, paving the way for more personalized approaches to asthma management.
Author: Siddhartha Devarakonda, Yize Li, Fernanda Martins Rodrigues, Sumithra Sankararaman, Humam Kadara, Chandra Goparaju, Irena Lanc, Kymberlie Pepin, Saiama N Waqar , Daniel Morgensztern, Jeffrey Ward , Ashiq Masood, Robert Fulton, Lucinda Fulton, Michael A Gillette, Shankha Satpathy, Steven A Carr, Ignacio Wistuba, Harvey Pass , Richard K Wilson, Li Ding , Ramaswamy Govindan
Description: Despite the strong relationship between smoking and lung cancer, up to 40% of patients with lung cancer have never smoked. The most common histological subtype of lung cancer in never- smokers is lung adenocarcinoma (LUAD). In this study whole-exome and RNA-sequencing data was generated on tumor and normal LUAD samples from never smokers to identify the potential genetic and environmental causes of lung cancer in these patients.
It was found that never smokers with lung cancer did not demonstrate a greater prevalence of cancer predisposing genes compared to never smokers, although a subset did show germline alterations in DNA repair genes. An additional subset had mutation signatures that were suggestive of passive exposure to cigarette smoke. Most strikingly, there was evidence of a subgroup of never smokers who had a distinct clinically relevant immune phenotype characterized by expression of clinically relevant immune checkpoint molecules and immune cell composition.
These findings suggest the existence of clinically actionable driver mutations in never smokers who develop lung cancer and emphasize the need for comprehensive molecular analyses of never-smoker lung cancers in the clinic.
Author: Jezreel Pantaleón García, Kevin J Hinkle, Nicole R Falkowski, Scott E Evans, and Robert P Dickson
Description:Healthy lungs are now known to harbor diverse and dynamic low-abundance bacterial communities. These microbiota correlate with lung immunity, but this relationship is incompletely understood.
This study modulated the lung immunity of healthy 8-9 week old adult mice (C57BL/6) using a exposure to an inhaled agent (Pam2-ODN) that decreases protection against bacterial and viral respiratory infections. Mice received either no exposure (“untreated”), PBS inhalation (“sham”), or Pam2-ODN treatment and were harvested 6 days after exposure. Comparison of the composition and character of the lung microbial communities revealed no differences between the three groups.
These findings suggest that the established correlation between lung microbiota and lung immunity is more likely attributable to the host response to respiratory microbiota rather than the microbiome being altered by variation in lung immunity. Although it should be cautioned that as these findings were derived from healthy lungs, this may not apply to conditions of airway, alveolar, or interstitial injury.
Description: Survival after lung transplantation is poor, with the leading cause of death being chronic rejection. Chronic rejection is manifested by fibrotic infiltration of the lung allograft, resulting in irreversible pulmonary dysfunction, termed chronic lung allograft dysfunction (CLAD). Given that individuals with chronic lung disease and poor lung function are known to display alterations in their microbiome the aim of this study was to determine whether the lung microbiome was an independent predictor of survival following lung transplantation.
Bronchoalveolar lavage fluid was collected from 134 patients 1 year after their lung transplant and used to assess bacterial DNA burden (total 16S rRNA gene copies per mL of BALF, quantified via droplet digital PCR) and bacterial community composition (determined by bacterial 16S rRNA gene sequencing). Within 500 days of sample collection, 24 (18%) patients developed CLAD, five (4%) died before confirmed development of CLAD, and 105 (78%) patients remained CLAD-free. It was found that the lung microbiome of those who developed CLAD or died was significantly different from those who survived CLAD-free. Lung bacterial burden was predictive of CLAD development or death (per log10 increase in burden, HR 2·49 [95% CI 1·38-4·48], p=0·0024) but no individual bacterial taxa could be definitively associated with CLAD development or death.
These findings demonstrate that the lung microbiome generally, and bacterial burden in particular, are novel and potentially modifiable risk factors for CLAD and death following lung transplantation.
DNA methylation at birth is associated with lung function development until age 26 years
Author: Nandini Mukherjee et al
Description: To date, there has been a lack of knowledge regarding the role of epigenetic markers at birth in the prediction of patterns of lung function development. This study explores, for the first time, the association between blood DNA methylation patterns at birth and lung function trajectories from childhood to adulthood. Epigenome-wide screening was applied to identify CpGs associated with lung function trajectories (forced expiratory volume in 1 s, forced vital capacity, their ratio, and forced expiratory flow at 25–75% of forced vital capacity) up to age 26, stratified by sex using heel prick DNA methylation (DNAm) from the Isle of Wight birth cohort. Replication was then performed in the Avon Longitudinal Study of Parents and Children (ALSPAC) using cord blood DNAm. Statistically significantly replicated CpGs were investigated for consistency in direction of association between cohorts, stability of DNAm over time, relevant biological processes and for association with gene expression. Differential DNAm of eight CpGs on genes (GLUL, MYCN, HLX, LHX1, COBL, COL18A1, STRA6, andWNT11) involved in developmental processes, were validated between the cohorts, and were found to predict lung function from age 10 to age 26 years. The results from this study support the development of epigenetic biomarkers for early prediction of health outcomes trajectories, allowing the potential for preventive and therapeutic interventions.
Description: The relationship between asthma and risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is controversial. This is in part due to the heterogenous nature of asthma in terms of its immunobiology, severity, and response to treatment. Therefore not all asthmatics are likely to respond to infection in the same manner. Thus, a more granular understanding of asthma, its subtypes and their relationship to SARS-CoV-2 is required.
In two large asthma cohorts, IMSA and SARP, the authors identified a subset of subjects who demonstrated low peripheral blood eosinophils accompanied by increased expression of the SARS-CoV-2 receptor ACE2 in bronchial epithelium, which was associated with upregulation of viral response genes as well as T-cell recruitment and activation within bronchoalveolar lavage cells. This indicates an overwhelming inflammatory response to SARS-CoV-2. This subset of patients demonstrated characteristics corresponding to risk factors for severe disease, including male sex and history of hypertension.
Therapies targeting the IFN family and T-cell-activating factors may be of benefit to this particular group of patients, and they deserve increased vigilance upon developing symptoms.
Author: Michael C. Peters, MD, ATS Member
Description: Individuals with asthma may be more likely to suffer from severe COVID-19, and within asthmatics certain subgroups may be at particularly high risk due to biological or demographic factors. In particular, it is hypothesized that differences in expression levels of ACE2 (angiotensin-converting enzyme 2), and TMPRSS2 (transmembrane protease serine 2), which are key mediators of viral infection of host cells, could influence risk. Therefore, the aim of this study was to determine factors associated with the expression of these genes in sputum cells.
Analysis of 330 participants in SARP-3 (Severe Asthma Research Program-3) and 79 healthy control subjects determined that expression levels of both ACE2 and TMPRSS2 in sputum cells were similar in asthmatics and healthy controls. However, among asthmatics, male sex, African American race, and history of diabetes mellitus were associated with higher expression levels. Intriguingly, use of inhaled corticosteroids (ICS) was associated with lower expression of ACE2 and TMPRSS2.
These findings provide a rationale for monitoring asthmatics who are male, African American, or have a history of diabetes mellitus for worse COVID-19 outcomes, but suggests ICS use may hold potential for decreasing susceptibility to infection and morbidity. Further prospective studies of COVID-19 outcomes in populations with asthma are warranted to explore these findings further.
Description: Chronic respiratory diseases are believed to arise in part due to the interaction of diverse atmospheric contaminants (respiratory microbes, pollution, allergens, and smoking) with the respiratory epithelium. The respiratory tract constitutes an elaborated line of defense to protect against such contaminants based on a unique cellular ecosystem, but remains incompletely understood. This is the first study to apply single-cell RNA profiling to biopsies from young healthy adults at distinct and well-identified macroanatomical regions in the airways.
In the framework of the Human Cell Atlas (HCA) consortium, a total of 77,969 cells were collected at 35 distinct locations, from the nose to the 12th division of the airway tree, in the airway epithelium of 10 volunteers and subject to single-cell RNA profiling.
The resulting atlas is composed of a high percentage of epithelial cells (89.1%) in addition to immune (6.2%) and stromal (4.7%) cells with distinct cellular proportions in different regions of the airways. It reveals differential gene expression between identical cell types (suprabasal, secretory, and multiciliated cells) from the nose (MUC4, PI3, SIX3) and tracheobronchial (SCGB1A1, TFF3) airways. By contrast, cell-type-specific gene expression is stable across all tracheobronchial samples.
Robust characterization of a single-cell cohort in healthy airways establishes a valuable resource for future investigations. Healthy volunteers are rarely accessible in most large-scale studies. The precise description of the continuum existing from the nasal epithelium to successive divisions of the airways and the stable gene expression profile of these regions better defines conditions under which relevant tracheobronchial proxies of human respiratory diseases can be developed.
Exuberant Fibroblast Activity Compromises Lung Function via ADAMTS4
Author: E. Kaitlynn Allen, PhD, G&G Section Social Media Lead
Description: Previous studies of host determinants of disease severity following respiratory viral infection have overwhelmingly focused on the role of migrating immune cells in mediating immunopathology. In this study, we identified activated lung fibroblasts as critical regulators of localized immune responses through the production of the extracellular matrix protease ADAMTS-4. In human cases of influenza, the level of ADAMTS-4 in the lower respiratory tract was a strong predictor of prolonged respiratory failure and mortality.
Age-of-onset information helps identify 76 genetic variants associated with allergic disease
Author: Gerard H. Koppelman, MD, PhD, Executive Committee Member
Description: The majority of studies of allergic disease to date have focused on incidence of disease rather than age at onset. The aim of this study was to identify genetic risk variants associated with the age at which symptoms of allergic diseases, including asthma, first develop. Self-reported age-of-onset information was available for 117,130 genotyped individuals of European ancestry from the UK Biobank study. For each individual, we identified the earliest age at which asthma, hay fever and/or eczema was first diagnosed and performed a genome-wide association study of this combined age-of-onset phenotype. We identified 50 variants with a significant independent association (P<3x10-8) with age-of-onset. We also determined that cases with early disease onset have a greater burden of allergy risk alleles than those with late disease onset. When considering both allergic status and age of onset a further 26 SNPs were identified. Of the 76 total variants, 18 were novel. We identified 81 likely target genes of these variants based on information from expression quantitative trait loci (eQTL) and non-synonymous variants, including ADAM15, FOSL2, TRIM8, BMPR2, CD200R1, PRKCQ, NOD2, SMAD4, ABCA7, and UBE2L3. In sum, these findings support the hypothesis that early and late-onset allergic diseases have partly distinct genetic architectures. GWAS of other complex diseases might also benefit from considering age-of-onset information.
Description: In this manuscript, we develop a polygenic risk score using genome-wide association study summary statistics of lung function from more than 400 000 participants from the UK Biobank and SpiroMeta, and demonstrate that it can be used to predict the diagnosis of COPD in nine population-based and case-control cohorts of multiple ethnicities. The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. This score uses more variants and larger sample sizes than previous studies and has been tested in a greater number of validation cohorts. As such, we show this new score is superior to previously described genetic risk scores and when combined with clinical risk factors (ie, age, sex, and smoking pack-years), shows improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The score was also associated with CT imaging phenotypes and patterns of reduced lung growth that could predispose individuals to COPD. These findings could have important implications for understanding the mechanisms underlying COPD and provide future opportunities for prevention and early intervention, as genomics becomes more widely adopted in health care.
GWAS Functional Variant rs2076295 Regulates Desmoplakin (DSP) Expression in Airway Epithelial Cells
Author: Xiaobo Zhou, PhD, Committee Member
Description: Intriguingly, the non-coding variant rs2076295 at 6q24, is associated with the susceptibility of Idiopathic Pulmonary Fibrosis (IPF) and with Chronic Obstructive Pulmonary Disease (COPD), but with opposite directions of effect for the risk allele. The aim of this study was to identify the causal gene and causal variant for the association in this locus to try and disentangle this further. Using CRISPR/Cas9 based genome editing approaches, the authors were able to demonstrate that rs2076295 is the functional variant that regulates DSP expression in airway epithelial cells. DSP encodes desmoplakin which forms cell-cell adhesion complexes enabling tissues to resist mechanical forces. Reduced levels of DSP, associated with the risk allele leads to increased expression of extracellular matrix genes and promotes migration of airway epithelial cells, which may explain the relationships with IPF and COPD. These findings demonstrate the applicability and utility of post-GWAS functional studies.
Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function
Author: Christine Wendt, MD
Description: Chronic obstructive pulmonary disease is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. The hypothesis of this study is that lung stromal cells activate pathological gene expression programs that support oncogenesis. This was explored by conducting a multiomics analysis of nonmalignant lung tissue to quantify the transcriptome, translatome, and proteome. The authors identified the activation of two distinct stromal gene expression programs that promote cancer initiation; and determined that which one was activated was dependent on lung function. In subjects with normal to mildly impaired lung function, the mammalian target of rapamycin (mTOR) pathway served as an upstream driver, whereas in subjects with severe airflow obstruction, pathways downstream of pathological extracellular matrix emerged. This work has important implications both for screening strategies and for personalized approaches to cancer treatment.
