Publication Spotlight

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Publication Spotlight

Publication Spotlight


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.

Authors: Sharina Kort, Marjolein Brusse-Keizer, Hugo Schouwink, Emanuel Citgez, Dr. Frans de Jongh, John van Putten, Ben van den Borne, Lisanne Kastelijn, Daiana Stolz, Milou Schuurbiers,, Michel van den Heuvel, Wouter H. van Geffen, Job van der Palen
Description: Much of the high morbidity associated with lung cancer is a consequence of advanced-stage disease at the time of initial diagnosis. Exhaled-breath contains a gas mixture of thousands of volatile organic compounds (VOCs) in low concentrations that reflect metabolic processes at tissue level and exhaled-breath analysis is based on shifts of this VOCs composition due to biochemical changes in different pathophysiologic processes. As such, an increasing number of studies suggest that exhaled-breath analysis of volatile organic compounds may have utility in the earlier diagnosis of lung cancer, however these studies tend to lack independent validation. In this multicentre study, a training dataset of 376 non-small cell lung cancer (NSCLC) and controls had real-time breath analysis performed using the AeonoseTM (the eNose Company, Zutphen, the Netherlands) a handheld electronic nose device featuring an array of three metal-oxide sensors, to create a prediction model. The combination of breath data and clinical parameters (sex, age, number of pack-years, smoking status, and COPD-status) demonstrated a sensitivity of 95%, specificity of 51%, a negative predictive value (NPV) of 94% with an area under the receiver operating characteristic curve (AUC) of 0.87 for the prediction of NSCLC. They then demonstrated that this model performed well in a validation population of 199 subjects with a sensitivity of 95%, specificity of 49%, NPV of 94%, and an AUC of 0.86. These promising findings provide further support for the use of non-invasive exhaled breath profiling in the earlier identification of lung cancer.

Lung Microbiota of Critically Ill Patients with COVID-19 Are Associated with Nonresolving Acute Respiratory Distress Syndrome

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. 

Description: In the absence of an accepted systems theory to interrogate synergistic responses, this study introduces an Omics-Based Interaction Framework (OBIF) to reveal molecular drivers of synergy through integration of statistical and biological interactions in synergistic biological responses. OBIF performs full factorial analysis of feature expression data from single versus dual exposures to identify molecular clusters that reveal synergy-mediating pathways, functions and regulators. As a practical demonstration, OBIF analyzed transcriptomic and proteomic data of a dyad of immunostimulatory molecules that induces synergistic protection against influenza A and revealed unanticipated NF-B/AP-1 cooperation that is required for antiviral protection. 
 The application of this framework allows discovery of molecular mechanisms behind dual exposures in highly synergistic or antagonistic phenotype models explored with a diverse array of Omics platforms and experimental conditions. Hence, unlike existing synergy quantification and prediction methods, OBIF is the first phenotype-driven "synergy interrogation" model that supports multiplatform discovery of synergy mechanisms at the molecular level. 
 This study provides both an insight into molecular mechanisms of lung epithelial innate immune responses against respiratory pathogens and a novel tool to study synergistic or antagonistic biological responses from Omics data.

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 MuraIvana V YangDavid A SchwartzYong HuangImre NothShwu Fan MaAstrid J YeoWilliam A FahyR Gisli JenkinsLouise 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. 

Authors: Yue Du, Kamran M Miah, Omar Habib, Helena Meyer-Berg, Catriona C Conway, Mariana A Viegas, Rebecca Dean, Dwiantari Satyapertiwi, Jincun Zhao, Yanqun Wang, Nigel J Temperton, Toby P E Gamlen, Deborah R Gill, Stephen C Hyde
Description: As the COVID-19 pandemic continues, it must be recognized that some elderly and immune-compromised populations are unable to raise an effective immune response against traditional vaccines. An alternative strategy is to use vector-mediated immunoprophylaxis (VIP) against SARS-CoV-2 infection. VIP involves the delivery of genes encoding neutralising antibodies into target cells via gene transfer; subsequently, the monoclonal antibody (mAb) protein is synthesised in vivo, secreted into the local milieu and ultimately the systemic circulation to engineer passive immunity. Viral vectors can be exploited for VIP, including recombinant Adeno-Associated Virus (rAAV) vectors that provide long-term and stable transgene expression with low vector immunogenicity and high tolerability.

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.

Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma

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.

Description: In this comprehensive and timely review, Brusselle and Koppelman discuss the role of biologic agents as efficacious add-on therapies for uncontrolled, severe eosinophilic asthma. 
The authors present evidence to suggest these therapies represent major breakthroughs for individuals with type 2–high severe asthma, significantly decreasing exacerbation rates and improving the quality of life and asthma control. They show that add-on therapy with mepolizumab, benralizumab, or dupilumab is glucocorticoid-sparing and reduces exacerbation rates in patients with oral glucocorticoid–dependent severe asthma, while tezepelumab has efficacy in a broader patient population, including patients with type 2–low severe asthma.
Brusselle and Koppelman also reflect on the future of biologics in severe asthma, including the urgent need for biomarkers that can better inform the choice of biologic therapy, and biomarkers that can predict and monitor therapeutic response; as well as the need for studies to explore the effects of long-term treatment encompassing diverse populations. If such advances can be made, they conclude that biologics will pave the way toward optimized precision medicine for patients with severe asthma.

Development of A Blood-Based Transcriptional Risk Score for Chronic Obstructive Pulmonary Disease

Authors: Matthew MollAdel BoueizAuyon GhoshAabida SaferaliSool LeeZhonghui XuJeong H YunBrian D HobbsCraig P HershDon D Sin , Ruth Tal-SingerEdwin K SilvermanMichael H ChoPeter J Castaldi 
Description: Chronic obstructive pulmonary disease (COPD) primarily develops in the setting of cigarette smoking exposure, however only a minority of smokers develop the disease and not all individuals will experience rapidly progressive lung function decline, exacerbations, and increased mortality. Identifying individuals at high risk of COPD and COPD progression is therefore crucial for focusing public health interventions and drug development.  The aim of this study was to determine whether a blood-based gene expression, or transcriptional risk score (TRS) for COPD adds value to a polygenic risk score (PRS) for predicting disease susceptibility and progression. Analyses were performed in 2,569 COPDGene participants and replication sought in 468 ECLIPSE COPD cases, all of whom smoked. The authors determined that a TRS including147 transcripts was predictive of COPD, COPD-related traits, and prospective FEV1 decline. Models including PRS, TRS, and clinical factors were more predictive of COPD and annualized FEV1 change compared to models with one risk score or clinical factors alone. The omic-based approach can lend insight into biological mechanisms, and offers the potential for development of personalized therapies. 
Authors: Victor E. Ortega; Michelle Daya;  Stanley J. Szefler;  Eugene R. Bleecker;   Vernon M. Chinchilli;   Wanda Phipatanakul;  Dave Mauger; Fernando D. Martinez; Esther Herrera-Luis;  Maria Pino-Yanes; Gregory A. Hawkins; Elizabeth J. Ampleford; Susan J. Kunselman; Corey Cox;   Leonard B. Bacharier;  Michael D. Cabana; Juan Carlos Cardet; Mario Castro;  Loren C. Denlinger; Celeste Eng; Anne M. Fitzpatrick;  Fernando Holguin;  Donglei Hu; Daniel J. Jackson;  Nizar Jarjour;  Monica Kraft;  Jerry A. Krishnan;  Stephen C. Lazarus; Robert F. Lemanske, Jr;  John J. Lima; Njira Lugogo; Angel Mak;  Wendy C. Moore; Edward T. Naureckas;  Stephen P. Peters;  Jacqueline A. Pongracic; Satria P. Sajuthi; Max A. Seibold; Lewis J. Smith;  Julian Solway;  Christine A. Sorkness; Sally Wenzel;  Steven R. White;  Esteban G. Burchard;  Kathleen Barnes;   Deborah A. Meyers; Elliot Israel;  Michael E. Wechsler,  for the NHLBI AsthmaNet.**
Description: Pharmacogenetic studies investigating the genetic architecture of therapeutic response to different asthma controller drugs have primarily consistent of whites of European descent. These studies identified novel loci associated with response to inhaled beta agonists and corticosteroids (ICS). A substantially smaller number of studies in African descent minorities identified novel pharmacogenetic loci for inhaled beta agonists not found in whites. Individuals with asthma from different ancestral backgrounds respond differently to long-acting beta agonist (LABA) and ICS making it important to understand pharmacogenetic mechanisms regulating therapeutic responsiveness in African descent minorities. We performed whole-genome admixture mapping in African descent minorities from the Best African Response to Drug (BARD) trials (Wechsler et al, N Engl J Med 2019) based on the composite superior response outcome comparing step up from low-dose ICS to quintupling (5xICS) versus doubling ICS (2.5xICS) or 5xICS versus adding LABA (salmeterol) to fluticasone 100mcg twice daily (FP100SAL). In 249 children, admixture mapping and subsequent fine mapping of a genome-wide chromosome 12 admixture mapping peak identified a significant admixture mapping peak containing RNFT2 and NOS1 (rs73399224) associated with superior responsiveness to 5xICS versus FP100SAL that was independently associated with exacerbations in ICS-treated African Americans from the SAGE cohort. In 267 adolescents/adults, we identified a peak on chromosome 22 associated with superior responsiveness to 5xICS versus 2.5xICS containing a locus adjacent to TPST2 (rs5752429) that was replicated in African Americans randomized to ICS in an independent asthma clinical trial This analysis of the BARD trial cohort is the first pharmacogenetic study to identify genome-wide significant and independently confirmed genetic variants associated with response to an asthma controller therapy in African descent minorities.

Metabo-Endotypes of Asthma Reveal Differences in Lung Function: Discovery and Validation in two TOPMed Cohorts

Author: Rachel S KellyKevin M MendezMengna HuangBrian D HobbsClary B ClishRobert GersztenMichael H ChoCraig E WheelockMichael J McGeachieSu H ChuJuan C CeledónScott T WeissJessica Lasky-SuNHLBI 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.

Genomic Profiling of Lung Adenocarrcinoma in Never-Smokers

Author: Siddhartha DevarakondaYize LiFernanda Martins RodriguesSumithra SankararamanHumam KadaraChandra GoparajuIrena LancKymberlie PepinSaiama N Waqar Daniel MorgenszternJeffrey Ward Ashiq MasoodRobert FultonLucinda FultonMichael A GilletteShankha SatpathySteven A CarrIgnacio WistubaHarvey Pass Richard K WilsonLi 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. 

Selective Modulation of the Pulmonary Innate Immune Response Does not Change Lung Microbiota in Healthy Mice

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. 

Author: Michael P Combs et al. 

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. 

Author: Matthew Camiolo, Marc Gauthier, Naftali Kaminski, Anuradha Ray, Sally E Wenzel

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.

COVID-19-related Genes in Sputum Cells in Asthma. Relationship to Demographic Features and Corticosteroids Fibroblast Activity Compromises Lung Function via ADAMTS4

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.

Author: Marie Deprez, Laure-Emmanuelle Zaragosi, Marin Truchi, Christophe Becavin, Sandra Ruiz García, Marie-Jeanne Arguel, Magali Plaisant, Virginie Magnone, Kevin Lebrigand, Sophie Abelanet, Frédéric Brau, Agnès Paquet, Dana Pe'er, Charles-Hugo Marquette, Sylvie Leroy, Pascal Barbry 

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.

Author: Blanca Himes PhD, Executive Committee Member
Description: One critical challenge for conducting large-scale genomic studies in biobanks, is the correct classification of complex and heterogeneous traits such as Chronic Obstructive Pulmonary Disease (COPD). This is complicated by the fact that spirometry measures are seldom available for biobank participants. Consequently, there is concern that the misclassification of COPD patients is preventing the discovery of the genetic variants that contribute to COPD. This study compared the agreement between different COPD definitions within the context of the UK biobank and the use of these different definitions influence GWAS results. 
The results indicated poor agreement between ICD-coded, self-reported and GOLD-based COPD definitions, and considerable differences in genomic risk loci identified via GWAS with each definition. A risk locus near HHIP was the only one shared across all three definitions, while two additional loci near CHRNA3 and CHRNA4 overlapped between the GOLD-based and ICD-coded COPD GWAS. As such the authors concluded that although the use of ICD codes and self-reports are convenient and efficient for phenotype classification in COPD, even large sample sizes achieved by their use may not yield association signals as strong as those of more objective criteria such as lung function measures. This may have important implications for GWAS of many complex traits within the context of large-scale biobanks.

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.

Author: Michael H. Cho, MD, Former Executive Committee Co-chair

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.

Author: Ann Chen Wu, MD, MPH, Nominating Committee Member  
Description: In this study, for the first time, we examined the real-world effectiveness of inhaled corticosteroids (ICS)  including the combination therapy consisting of ICS and long-acting beta agonists (LABAs), considering patterns of use over a 15-year time period. We used data from the Kaiser Permanente Northern California multi-ethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) Cohort which comprises longitudinal electronic health record data of over 100,000 people. We assessed longitudinal asthma-related events, such as ambulatory office visits, hospitalizations, emergency department (ED) visits, and fills of ICS and ICS-LABA combination; and defined Asthma exacerbations as an asthma-related ED visit, hospitalization, or oral corticosteroid (OCS) burst. We found that in this real world setting ICS-LABA therapy reduced all types of exacerbations by a factor of 1.76 (95% CI (1.06, 2.93),  p = 0.03) per day and, specifically, bursts per day by a factor of 1.91 (95% CI (1.04, 3.53),  p = 0.037). We concluded that ICS-LABA therapy was significantly associated with fewer asthma-related exacerbations in a large population of individuals with asthma who were followed for 15 years.

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.

Author: Dr. Victor Ortega, Co-Chair, Section on Genetics and Genomics
Description: Ortega and colleagues comprehensively evaluated the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in 1,693 non-Hispanic Whites, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking using deep DNA sequencing of the gene encoding α1-antitrypsin, SERPINA1. This integrative sequencing study is the first to perform deep gene sequencing in combination with α1-antitrypsin concentrations in multiple ethnic groups to detect the cumulative effects of PI Z, S, and additional, rare SERPINA1 variants combined and independently.