1. A novel whole blood gene expression signature for asthma, dermatitis and rhinitis multimorbidity in children and adolescents
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Cheng-Jian Xu, Stefano Guerra, Erick Forno, Mübeccel Akdis, Anna Bergström, Edna Acosta-Pérez, Thomas Keil, Nadia Boutaoui, Glorisa Canino, Marie Standl, Stéphane Joly, Jesús Ibarluzea Maurolagoitia, Camille Ménard, Valérie Siroux, Loreto Santa Marina Rodríguez, Joachim Heinrich, Josep M. Antó, Judith Garcia-Aymerich, Jordi Sunyer, Juan R. González, Inger Kull, Yale Jiang, Mariona Bustamante, Olena Gruzieva, Magnus Wickman, Nathanaël Lemonnier, Elisabeth Thiering, Erik Melén, Daniel Aguilar, Juan C. Celedón, Gerard H. Koppelman, Pierre Hainaut, Jean Bousquet, Wei Chen, Cezmi A. Akdis, Groningen Research Institute for Asthma and COPD (GRIAC), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Sachs' Children's Hospital, Institute of Environmental Medicine, Karolinska Institutet, Stockholm., Children's Hospital of Pittsburgh of UPMC [Etats-Unis], School of Medicine, Tsinghua University, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Biologie cellulaire des infections virales – Cell biology of viral infection, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Biomedical Research Networking Center in Hepatic and Digestive Diseases [Barcelone, Espagne] (CIBEREHD), Instituto de Salud Carlos III [Madrid] (ISC), University of Puerto Rico (UPR), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Universitat Pompeu Fabra [Barcelona] (UPF), University of Arizona, German Research Center for Environmental Health - Helmholtz Center München (GmbH), Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Instituto de Investigación Sanitaria Biodonostia - San Sebastián, Ludwig Maximilians University of Munich, Uppsala University Hospital, Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Epidemiology and Health Economics [Berlin, Germany] (Institute of Social Medicine), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institute for Clinical Epidemiology and Biometry [Würzburg, Germany], Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Beatrix Children's Hospital/University Medical Center Groningen, GRIAC Research Institute [Groningue, Pays-Bas], University Medical Center Groningen [Groningen] (UMCG), Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), MACVIA-France, Montpellier, European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA), Institut National de la Santé et de la Recherche Médicale, Inserm Institut Universitaire de France, IUF Centre National de la Recherche Scientifique, CNRS: USR3010, We thank all other investigators of the MeDALL Study Group for their advices and support: Annesi-Maesano Isabella, Baiz Nour, Bedbrook Anna, Cambon-Thomsen Anne, Jacquemin Benedicte, Kauffmann Francine, Pin Isabelle, Rial-Sebbag Emmanuelle, Nadif Rachel, Basagna Xavier, Benet Mora Marta, Kogevinas Manolis, Lavi Iris, Mestre Jordi, Pinart Mariona, Colli Matthias, Hettler-Chen Chih-Mei, Hohmann Cynthia, Keller Teresa, Lau Susanne, Schietinger Andrea, van Hofmann Ingrid, Worm Margitta, Zuberbier Torsten, Pison Christophe, Kerkhof Marjan, Nawijn Martijn C., van Oosterhout Antoon J. M., Wijmenga Cisca, Bachert Claus, Coquet Jonathan, Hammad Hamida, Lambrecht Bart, Saeys Yvan, Haahtela Tari, Hanninen Sinikka, Makela Mika, Reitamo Sakari, von Hertzen Leena, Klimek Magdalena, Kowalski Marek, Carlsen Kai Hakon, Lodrup-Carlsen Karin C., Baar Alexandra, Lupinek Christian, Pahr Sandra, Valenta Rudolf, van de Veen Willem, Andersson Niklas, Ballardini Natalia, Johansson SGO, Kumar Ashish, Merid Simon Kebede, Thacher Jesse, van Hage Marianne, Westman Marit, Yazdanbakhsh Maria, Tischer Christina, Brunekreef Bert, Gehring Ulrike, Smit Henriette A, Le Naour St?phanie, Smagghe Delphine, Albang Richard, Arno Albert, Mascaro Angels, Roda Xavier, Sanchez Cristina, Vega Mireia, Baumgartner Ursula, Neubauer Angela, Stolz Franck, McEachan Rosie, Oddie Sam, Petherick Emily, Raynor Pauline, Waiblinger Dagmar, Wright John, Martinez Fernando D., De Carlo Giuseppe, Palkonen Susanna, Salvi Roberta, Wecksell Per-Ake, Bindslev-Jensen Carsten, Eller Esben, Steensen Jens Peter, Forestiere Francesco, Narduzzi Silvia, Porta Daniela. We acknowledge IRT BIOASTER for hosting MeDALL data production team: Alain Troesch and Nathalie Gar?on, Vincent Lotteau from INSERM for kindly hosting part of MeDALL data production, and members of the CNRS USR3010: Charles Auffray, St?phane Ballereau and Johann Pellet, plus Bertrand De Meulder and Diane Lefaudeux from U-BIOPRED project for the active discussions on sample selection and analyses. We thank Dieter Maier for the knowledge management platform and the data sharing between partners. The authors thank all children and parents participating in the BAMSE cohort, the nurses, and other staff working with the BAMSE project. The authors thank all the families for their participation in the GINIplus study. Furthermore, we thank all members of the GINIplus Study Group for their excellent work. The GINIplus Study group consists of the following: Institute of Epidemiology I, Helmholtz Zentrum M?nchen, German Research Centre for Environmental Health, Neuherberg (Heinrich J, Br?ske I, Schulz H, Flexeder C, Zeller C, Standl M, Schnappinger M, Ferland M, Thiering E, Tiesler C), Department of Pediatrics, Marien-Hospital, Wesel (Berdel D, von Berg A), Ludwig-Maximilians-University of Munich, Dr von Hauner Children's Hospital (Koletzko S), Child and Adolescent Medicine, University Hospital rechts der Isar of the Technical University Munich (Bauer CP, Hoffmann U), IUF- Environmental Health Research Institute, D?sseldorf (Schikowski T, Link E, Kl?mper C). The authors thank all the families for their participation in the INMA project. A full list of INMA researchers can be found at http://www.proyectoinma.org/presentacion-inma/listado-investigadores/listado-investigadores.html., Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Ludwig-Maximilians University [Munich] (LMU), Julius-Maximilians-Universität Würzburg (JMU), Contre les MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon (MACVIA-LR), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-European Innovation Partnership on Active and Healthy Ageing Reference Site (EIP on AHA), Commission Européenne-Commission Européenne-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)
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0301 basic medicine ,Allergy ,Adolescent ,multimorbidity ,IMPACT ,[SDV]Life Sciences [q-bio] ,Immunology ,Interleukin 5 receptor alpha subunit ,IL1RL1 ,ECZEMA ,Disease ,Article ,DISEASE ,MECHANISMS ,Transcriptome ,03 medical and health sciences ,transcriptomics ,0302 clinical medicine ,rhinitis ,Hypersensitivity ,Humans ,Immunology and Allergy ,Medicine ,Child ,Gene ,Asthma ,atopic dermatitis ,business.industry ,CHILDHOOD ASTHMA ,Atopic dermatitis ,asthma ,medicine.disease ,Rhinitis, Allergic ,Atopic Dermatitis ,Multimorbidity ,Rhinitis ,Transcriptomics ,3. Good health ,ALPHA ,030104 developmental biology ,030228 respiratory system ,MEDALL ,RNA ,business - Abstract
International audience; Background: Allergic diseases often occur in combination (multimorbidity). Human blood transcriptome studies have not addressed multimorbidity. Large-scale gene expression data were combined to retrieve biomarkers and signaling pathways to disentangle allergic multimorbidity phenotypes. Methods: Integrated transcriptomic analysis was conducted in 1233 participants with a discovery phase using gene expression data (Human Transcriptome Array 2.0) from whole blood of 786 children from three European birth cohorts (MeDALL), and a replication phase using RNA Sequencing data from an independent cohort (EVA-PR, n = 447). Allergic diseases (asthma, atopic dermatitis, rhinitis) were considered as single disease or multimorbidity (at least two diseases), and compared with no disease. Results: Fifty genes were differentially expressed in allergic diseases. Thirty-two were not previously described in allergy. Eight genes were consistently overexpressed in all types of multimorbidity for asthma, dermatitis, and rhinitis (CLC, EMR4P, IL5RA, FRRS1, HRH4, SLC29A1, SIGLEC8, IL1RL1). All genes were replicated the in EVA-PR cohort. RT-qPCR validated the overexpression of selected genes. In MeDALL, 27 genes were differentially expressed in rhinitis alone, but none was significant for asthma or dermatitis alone. The multimorbidity signature was enriched in eosinophil-associated immune response and signal transduction. Protein-protein interaction network analysis identified IL5/JAK/STAT and IL33/ST2/IRAK/TRAF as key signaling pathways in multimorbid diseases. Synergistic effect of multimorbidity on gene expression levels was found. Conclusion: A signature of eight genes identifies multimorbidity for asthma, rhinitis, and dermatitis. Our results have clinical and mechanistic implications, and suggest that multimorbidity should be considered differently than allergic diseases occurring alone.
- Published
- 2020
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