Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects

Busch, Robert S.; Hobbs, Brian D.; Zhou, Jin; Castaldi, Peter J.; McGeachie, Michael J.; Hardin, Megan; Hawryłkiewicz, I; Śliwiński, Paweł; Yim, Jae Joon; Kim, Woo Jin; Kim, Deog K.; Agustí, Àlvar; Make, Barry J.; Crapo, James D.; Calverley, Peter M.A.; Donner, Claudio F.; Lomas, David A.; Wouters, Emiel; Vestbo, Jørgen; Tal‐Singer, Ruth; Bakke, Per; Gulsvik, Amund; Litonjua, Augusto A.; Sparrow, David; Paré, Peter D.; Levy, Robert D.; Rennard, Stephen I.; Beaty, Terri H.; Hokanson, John E.; Silverman, Edwin K.; Cho, Michael H.; Laird, Nan M.; Lange, Christoph; Cho, Michael; Santorico, Stephanie A.; McDonald, Merry-Lynn; Wan, Emily S.; Hetmanski, Jacqueline B.; Parker, Margaret M.; Hobbs, Brian D.; El-Bouiez, Adel; Qiao, Dandi; Halper-Stromberg, Eitan; Begum, Ferdouse; Won, Sungho; Lynch, David A.; Hoffman, Eric A.; Humphries, Stephen; Judy, Philip F.; Regan, Elizabeth A.; Ross, James C.; Estépar, Raúl San Jośe; Stoel, Berend C.; Tschirren, Juerg; Rikxoort, Eva M. van; Ginneken, Bram van; Wilson, Carla; Qaisi, Mustafa Al; Gray, Teresa; Kluiber, Alex; Mann, Tanya; Sieren, Jered; Stinson, Douglas; Schroeder, Joyce; Beek, Edwin van; Jensen, Robert L.; Everett, Douglas; Faino, Anna; Strand, Matt; Wilson, Carla; Kinney, Gregory L.; Lutz, Sharon M.; Young, Kendra A.; Pratte, Katherine; Duca, Lindsey M.; Curtis, Jeffrey L.; Martínez, Carlos H.; Pernicano, Perry G.; Alapat, Philip; Bandi, Venkata; Atik, Mustafa A.; Boriek, Aladin M.; Guntupalli, Kalpatha; Guy, Elizabeth; Parulekar, Amit; Nachiappan, Arun C.; DeMeo, Dawn L.; Hersh, Craig P.; Washko, George; Jacobson, Francine L.; Barr, R. Graham; Thomashow, Byron; Austin, John; D’Souza, Belinda; Pearson, Gregory; Rozenshtein, Anna; Washington, Lacey; McAdams, H. Page; McEvoy, Charlene; Tashjian, Joseph H.; Hansel, Nadia N.; Brown, Robert; Horton, Karen M.; Putcha, Nirupama; Adami, Alessandra; Pórszász, János; Fischer, Hans; Budoff, Matthew J.; Rossiter, Harry B.; Lan, Charlie; Wendt, Christine; Bell, Brian; Foreman, Marilyn G.; Westney, Gloria; Berkowitz, Eugene A.; Bowler, Russell P.; Lynch, David S.; Rosiello, Richard; Pace, David; Criner, Gerard J.; Ciccolella, David; Cordova, Francis; Dass, Chandra; D’Alonzo, Gilbert E.; Desai, Parag; Jacobs, Michael E.; Kelsen, Steven; Kim, Victor; Mamary, A. James; Marchetti, Nathaniel; Satti, Aditi; Shenoy, Kartik; Steiner, Robert M.; Swift, Alex; Swift, Irene; Vega-Sanchez, Maria Elena; Dransfield, Mark T.; Bailey, William C.; Wells, James M.; Bhatt, Surya P.; Nath, Hrudaya; Ramsdell, Joe; Friedman, Paul J.; Soler, Xavier; Yen, Andrew; Comellas, A.P.; Newell, John D.; Thompson, Brad; Han, MeiLan K.; Kazerooni, Ella A.; Martínez, Carlos José Álvarez; Billings, Joanne; Allen, Tadashi; Chandra, Divay; Weissfeld, Joel L.; Fuhrman, Carl R.; Bon, Jessica; Adams, Sandra G.; Maselli‐Caceres, Diego; Ruiz, Mario E.; Ivanov, Yavor; Kostov, Kosta; Bourbeau, Jean; FitzGerald, Mark; Hernández, Paul; Killian, K. J.; Maltais, F.; OʼDonnell, Dennis; Krepelka, J.; Quinn, David I.; Košnik, Mitja; Sauleda, Jaume; Feschenko, Yuriy; Gavrisyuk, V.; Yashina, L.; Monogarova, Nadiya; Singh, Dave; Wedzicha, Jadwiga A.; Anzueto, Antonio; Braman, Sidney S.; Casaburi, Richard; Giessel, Glenn; Gotfried, Mark H.; Greenwald, Gilbert S.; Hanania, Nicola A.; Mahler, D.A.; Rochester, Carolyn L.; Schuller, Dan; Sharafkhaneh, Amir; Siler, Thomas; Wanner, Adam; Wise, Robert A.; ZuWallack, Richard; Coxson, Harvey O.; Edwards, Lisa; Singer, Ruth Tal; Agustí, Àlvar; Calverley, P. M. A.; Celli, Bartolomé R.; Crim, Courtney; Miller, Brian C.; MacNee, William; Wouters, Emiel F.M.; Yates, Julie; Benditt, Joshua O.; Criner, G.J.; DeCamp, Malcolm M.; Diaz, Phillip; Ginsburg, Mark E.; Kaiser, Larry R.; Katz, MJ; Krasna, Mark J.; MacIntyre, Neil R.; McKenna, Robert J.; Martínez, Fernando D.; Mosenifar, Zab; Reilly, John J.; Ries, Andrew L.; Scanlon, Paul D.; Sciurba, Frank C.; Utz, James P.

doi:10.1165/rcmb.2016-0331oc

Cited by 61 publications

(35 citation statements)

References 57 publications

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“…In macrophages, elevated levels of NOTCH ligands such as DNER have been associated with respiratory diseases, and NOTCH signaling was shown to be upstream of IFN- induction in cigarette-exposed animals (Ballester-López et al, 2019;Reyfman et al, 2019) as well as in COPD patients (Ballester-López et al, 2019). Of interest, SNPs in DNER have been associated with a higher risk of COPD (Busch et al, 2017;Hancock et al, 2012). While crosstalk between NOTCH, WNT, and TGF-β pathways are known for nonsmall cell lung cancer (Li et al, 2011;Ohnuki et al, 2014), this has not been reported yet for COPD.…”

Section: Discussionmentioning

confidence: 99%

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Baßler

Fujii

Kapellos

et al. 2020

Preprint

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Despite the epidemics of chronic obstructive pulmonary disease (COPD), the cellular and molecular mechanisms of this disease are far from being understood. Here, we characterize and classify the cellular composition within the alveolar space and peripheral blood of COPD patients and control donors using a clinically applicable single-cell RNA-seq technology corroborated by advanced computational approaches for: machine learning-based cell-type classification, identification of differentially expressed genes, prediction of metabolic changes, and modeling of cellular trajectories within a patient cohort. These high-resolution approaches revealed: massive transcriptional plasticity of macrophages in the alveolar space with increased levels of invading and proliferating cells, loss of MHC expression, reduced cellular motility, altered lipid metabolism, and a metabolic shift reminiscent of mitochondrial dysfunction in COPD patients. Collectively, single-cell omics of multi-tissue samples was used to build the first cellular and molecular framework for COPD pathophysiology as a prerequisite to develop molecular biomarkers and causal therapies against this deadly disease.

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Section: Discussionmentioning

confidence: 99%

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Baßler

Fujii

Kapellos

et al. 2020

Preprint

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“…SNPs in a group of genes have been found to be associated with COPD 39 40. Remarkably, the protein products encoded by several of these genes, for example, CHRM3, have become pharmacological targets for the treatment of COPD and asthma 39.…”

Section: Discussionmentioning

confidence: 99%

Endotype-driven prediction of acute exacerbations in chronic obstructive pulmonary disease (EndAECOPD): protocol for a prospective cohort study

Xiao

Mao

et al. 2019

BMJ Open

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IntroductionCurrent strategies for the prevention of acute exacerbations in chronic obstructive pulmonary disease (COPD) are primarily based on clinical measurements but fail to target the pathophysiological mechanisms, namely endotypes, of the disease. Studies identifying endotypes underlying exacerbation susceptibility and discovering specific biomarkers may lead to the development of targeted therapeutics but are lacking. This study aims to assess a broad spectrum of biomarkers at multiple biological levels (genetics, airway inflammation and respiratory microbiome) for their ability in predicting acute exacerbations of COPD, thus enables high-resolution disease endotyping and may lead to precision treatment of the disease.Methods and analysisIn this prospective cohort study, participants with stable COPD (n=600) will be recruited and assessed for demographics, symptom scores, spirometry, medication use and comorbidities at baseline. Blood will be obtained for genotyping variants in a panel of nine genes. Induced sputum will be collected for the profile of microbiota using 16S rRNA gene sequencing, quantification of bacterial load, inflammatory mediators assay and sputum cytometry. Participants will be followed up for their exacerbations till 12 months and reassessed for the clinical measurements as baseline. The primary outcomes are total number of exacerbations, severe exacerbations, moderate exacerbations and time to first exacerbation. The secondary outcomes are changes in lung function and symptom scores. The effect of biomarkers representing genetic variants, airway inflammation and respiratory microbiome on predicting the frequent exacerbator phenotype and exacerbation frequency will be analysed with multivariable modelling, and time to first exacerbation with a Cox regression model.Ethics and disseminationThe study has been approved by the Clinical Trial and Biomedical Ethics Committee of West China Hospital of Sichuan University (No. 2018–298). The results of the study will be published on peer-reviewed journals.Trial registration numberChiCTR1800019063.

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“…In a recent meta-analysis study, Busch and coworkers [16] genotyped 3346 single nucleotide polymorphisms (SNP) in 2588 cases (1803 severe COPD) and 1782 controls from four cohorts. They analyzed association testing with COPD, combining their results with existing genotyping data from 6633 cases (3497 severe COPD) and 5704 controls.…”

Section: Geneticsmentioning

confidence: 99%

Genetics Association and Epigenetic Changes in COPD

Malhotra¹,

Vaarala²

2018

COPD - An Update in Pathogenesis and Clinical Management

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Genome-wide association studies (GWASs) have successfully identified susceptibility loci associated with COPD. The genes mapped on these loci, eg The FAM13A gene (family with sequence similarity 13, member A), provide a new approach to understand the COPD pathology. Furthermore, heavy smoking is reported to correlate with altered methylation and epigenetic changes of multiple genes in small airway cells. These changes have been shown to be associated with the severity of COPD. It is likely that smoking-induced changes in epigenetic control of gene expression result in genetically vulnerable individual's results in reduced tissue repair, tissue damage and persistent inflammation associated with COPD pathophysiology.

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Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects

Cited by 61 publications

References 57 publications

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Alterations of multiple alveolar macrophage states in chronic obstructive pulmonary disease

Endotype-driven prediction of acute exacerbations in chronic obstructive pulmonary disease (EndAECOPD): protocol for a prospective cohort study

Genetics Association and Epigenetic Changes in COPD

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