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.

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.