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: Constanze A Jakwerth1 2, Markus Weckmann2 3 4 5, Sabina Illi2 6 7, Helen Charles1 2, Ulrich M Zissler1 2, Madlen Oelsner1 2, Ferdinand Guerth 1 2, Jimmy Omony2 6 7, Sai Sneha Priya Nemani2 4 5, Ruth Grychtol2 8 9, Anna-Maria Dittrich2 8 9, Chrysanthi Skevaki2 10, Svenja Foth2 11, Stefanie Weber2 11, Miguel A Alejandre Alcazar2 12 13 14 15, Silke van Koningsbruggen-Rietschel2 15, Robert Brock2 15, Samira Blau2 15, Gesine Hansen2 8 9 16, Thomas Bahmer 2 5 17, Klaus F Rabe2 5 18, Folke Brinkmann2 3 4 5, Matthias Volkmar Kopp4 19 5, Adam M Chaker1 20, Bianca Schaub2 21 7, Erika von Mutius2 6 21, Carsten B Schmidt-Weber1 2
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 Patchen1, Pallavi Balte2, Traci M Bartz3, R Graham Barr2, Myriam Fornage4, Mariaelisa Graff5, David R Jacobs Jr6, Ravi Kalhan7, Rozenn N Lemaitre3, George O'Connor8, Bruce Psaty3, Jungkyun Seo5, Michael Y Tsai9, Alexis C Wood10, Hanfei Xu11, Jingwen Zhang11, Sina A Gharib12, Ani Manichaikul13, Kari North4, Lyn M Steffen5, Josée Dupuis10 14, Elizabeth Oelsner2, Dana B Hancock15, Patricia A Cassano1 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: Min Hyung Ryu , Jeong H Yun , Jarrett D Morrow, Aabida Saferali, Peter Castaldi , Robert Chase, Meryl Stav,
Zhonghui Xu, Igor Barjaktarevic, MeiLan Han, Wassim Labaki, Yvonne J Huang, Stephanie Christenson, Wanda O'Neal,
Russell Bowler, Don D Sin, Christine M Freeman, Jeffrey L Curtis, Craig P Hersh
Description: To gain insights into why some patients are more prone to COPD exacerbations, authors conducted whole blood transcriptomic analyses in over 3600 research participants. Study subjects included former and current smokers with a wide range of spirometric measures in the COPDGene study, a prospective longitudinal cohort. Gene expression patterns were significantly different in subjects who reported having had exacerbations than those who did not have any exacerbation (during 1 year prior to the study visit). Many of these genes were linked to an increased risk of subsequent exacerbations. Utilizing computational cell-type deconvolution (CIBERSORTx), authors found several immune cell subtypes (T lymphocyte populations) in blood that were associated with a higher exacerbation annual rate. Specifically, lower circulating CD4+ subpopulations were linked to increased exacerbations. Furthermore, cell-type-specific gene expressions in neutrophils (TLR2) and CD4+ T-lymphocyte (B3GALT2, BTLA, CCR6, ZBTB25) were associated with increased prospective exacerbation rate. The authors performed a replication study in ECLIPSE, another large COPD study with blood transcriptomic data and rich exacerbation measures. They found several genes and cell-type-specific genes that replicated. Additionally, the authors performed flow cytometry analyses in SPIROMICS sub-study, where multi-center immune profiling was performed and analyzed with exacerbation data. Here, lower circulating T lymphocytes (but more activated) were associated with an increased risk of exacerbation. Taken together, this work provides robust omics-based evidence to support the notion that immune dysregulation plays a part in COPD exacerbation-susceptible endotype and provides potential targets for future therapeutic interventions.
Genetic Modifiers of Cystic Fibrosis Lung Disease Severity: Whole Genome Analysis of 7,840 Patients
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.
Authors: Daphne M Moutsoglou, Jasmine Tatah, Sasha Z Prisco, Kurt W Prins, Christopher Staley, Sharon Lopez, Madelyn Blake, Levi Teigen, Felipe Kazmirczak, E Kenneth Weir, Amanda J Kabage, Weihua Guan, Alexander Khoruts, Thenappan Thenappan
Description: Perivascular inflammation plays a critical role in driving pulmonary vascular remodeling that leads to pulmonary arterial hypertension (PAH). However, the mechanisms that initiate and perpetuate immune dysregulation and perivascular inflammation in PAH remain unclear. Investigation of the gut microbiome may provide answers. In this study complementary 16S ribosomal RNA gene and shotgun metagenomics sequencing was performed on stool from patients with PAH, family control subjects, and healthy control subjects, in order to characterize the gut microbiome. The results demonstrated that PAH patients have less diverse gut microbiomes and a distinct gut microbial signature at the phylogenetic level. They had reduced relative abundances of gut bacteria that contain encoding genes for the production of anti-inflammatory metabolites (short-chain fatty acids and secondary bile acids) and increased relative abundances of gut bacteria that contain encoding genes for the production of trimethylamine, a proinflammatory metabolite. Reduced gut diversity correlated with the severity of disease. Consistent with these gut microbial changes, patients with PAH had relatively lower plasma concentrations of SCFAs and secondary bile acids. Interestingly, the changes in the gut microbiome and circulating microbial metabolites between patients with PAH and family control subjects were not as substantial as the differences between patients with PAH and healthy control subjects. This study provides a mechanistic link between gut dysbiosis, systemic inflammation, and pulmonary arterial hypertension and provide a compelling rationale to investigate strategies such as microbiota transplantation therapy to target the gut microbiome for the treatment of PAH.
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: Raphael Borie, Jonathan Cardwell, Iain R Konigsberg, Camille M Moore, Weiming Zhang, Sarah K Sasse, Fabienne Gally, Evgenia Dobrinskikh, Avram Walts, Julie Powers, Janna Brancato, Mauricio Rojas, Paul J Wolters , Kevin K Brown, Timothy S Blackwell, Tomoko Nakanishi, J Brent Richards, Anthony N Gerber, Tasha E Fingerlin, Norman Sachs, Sara L Pulit, Zachary Zappala, David A Schwartz , Ivana V Yang
Description: Idiopathic pulmonary fibrosis (IPF) is a complex and incurable disease. Genetic risk factors explain a large portion of attributable risk. An understanding of the variants underlying this risk offer the possibility to identify disease before irreversible scarring occurs and to develop additional therapeutic targets. The authors previously identified 10 common variants that in aggregate account for at least 40% of the risk of IPF, of these the MUC5B promoter variant, rs35705950, was the strongest genetic risk variant for IPF. However, a more comprehensive analysis of the MUC5Blocus and other IPF-associated genetic loci is necessary to better understand disease pathogenesis and to guide disease diagnosis and treatment. To investigate the functional relevance of common genetic IPF risk variants, the authors performed genome, transcriptome, and methylome analyses on lung tissue from IPF and control subjects, and co-localization and mediation analysis of eQTL and mQTL with genetic loci to prioritize potential causal risk variants. They identified 27 eQTLs in controls and 24 eQTLs in cases. Among these signals, the lead variant rs35705950 associated with expression of MUC5B and rs2076295 associated with expression of DSP in both cases and controls. mQTL analysis identified CpGs in gene bodies of MUC5B (cg17589883) and DSP (cg08964675) associated with the lead variants in these two loci. The authors also report strong co-localization of eQTL/mQTL and genetic signal in MUC5B(rs35705950) and DSP (rs2076295). Functional validation of the mQTL in MUC5B using luciferase reporter assays demonstrated that the CpG resides within a putative internal repressor element. These findings establish a relationship between the common IPF genetic risk variants rs35705950 and rs2076295 with respective changes in MUC5B and DSP expression and methylation,and provide additional evidence that both MUC5B and DSP are involved in the etiology of IPF.
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: Sharina Kort, Marjolein Brusse-Keizer Hugo Schouwink, Emanuel Citgez, Dr. Frans de Jongh, John van Putten, Be 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.
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.
OBIF: an omics-based interaction framework to reveal molecular drivers of synergy
Authors: Jezreel Pantaleón García, Vikram V Kulkarni, Tanner C Reese, Shradha Wali, Saima J Wase, Jiexin Zhang, Ratnakar Singh, Mauricio S Caetano, Humam Kadara, Seyed Javad Moghaddam, Faye M Johnson, Jing Wang, Yongxing Wang, Scott E Evans
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 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.
Lung directed antibody gene transfer confers protection against SARS-CoV-2 infection
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.
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.
Biologic Therapies for Severe Asthma
Authors: Guy G Brusselle, Gerard H Koppelman
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 Moll, Adel Boueiz, Auyon Ghosh, Aabida Saferali, Sool Lee, Zhonghui Xu, Jeong H Yun, Brian D Hobbs, Craig P Hersh, Don D Sin , Ruth Tal-Singer, Edwin K Silverman, Michael H Cho, Peter 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 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.
Genomic Profiling of Lung Adenocarrcinoma in Never-Smokers
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.
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.