Nathanaël Lemonnier1, Erik Melén2,3, Yale Jiang4,5, Stéphane Joly6, Camille Ménard6, Daniel Aguilar7, Edna Acosta-Perez8, Anna Bergström3, Nadia Boutaoui4, Mariona Bustamante9,10,11, Glorisa Canino8, Erick Forno4, Juan Ramon González9, Judith Garcia-Aymerich9, Olena Gruzieva3, Stefano Guerra9,12, Joachim Heinrich13,14, Inger Kull15, Jesús Ibarluzea Maurolagoitia11,16, Loreto Santa-Marina Rodriguez11, Elisabeth Thiering13,17, Magnus Wickman18, Cezmi Akdis19, Mübeccel Akdis19, Wei Chen4,20, Thomas Keil21,22,23, Gerard H Koppelman24,25, Valérie Siroux1, Cheng-Jian Xu24,25, Pierre Hainaut1, Marie Standl13, Jordi Sunyer9, Juan C Celedón4, Josep Maria Antó9, Jean Bousquet26,27,28,29. 1. Institute for Advanced Biosciences, UGA-INSERM U1209-CNRS UMR5309, Allée des Alpes, France. 2. Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Sachs' Children's Hospital, Stockholm, Sweden. 3. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 4. Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA. 5. School of Medicine, Tsinghua University, Beijing, China. 6. CIRI, International Center for Infectiology Research, Inserm, Lyon, France. 7. Biomedical Research Networking Center in Hepatic and Digestive Diseases (CIBEREHD), Barcelona, Spain. 8. Behavioral Sciences Research Institute, University of Puerto Rico, San Juan, Puerto Rico. 9. ISGlobal, Barcelona Institute for Global Health, Barcelona, Spain. 10. Universitat Pompeu Fabra (UPF), Barcelona, Spain. 11. Instituto de Salud Carlos III, Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain. 12. Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, USA. 13. Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany. 14. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Inner City Clinic, University Hospital of Munich (LMU), Munich, Germany. 15. Department of Clinical Science and Education, Sodersjukhuset, Karolinska Institute, Stockholm, Sweden. 16. BIODONOSTIA, Instituto de Investigación Sanitaria, Donostia-San Sebastián, Spain. 17. Division of Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany. 18. Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna, Sweden. 19. Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland. 20. Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA. 21. Institute of Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Berlin, Germany. 22. Institute for Clinical Epidemiology and Biometry, University of Würzburg, Würzburg, Germany. 23. Institute for Health Resort Medicine and Health Promotion, Bavarian Health and Food Safety Authority, Bad Kissingen, Germany. 24. Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 25. GRIAC Research Institute, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 26. MACVIA-France, Fondation partenariale FMC VIA-LR, Montpellier, France. 27. Ageing and Chronic Diseases, Epidemiological and Public Health Approaches, Université Versailles St-Quentin-en-Yvelines, UMR-S 1168, Montigny le Bretonneux, France. 28. Euforea, Brussels, Belgium. 29. Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Comprehensive Allergy Center, Berlin, Germany.
Abstract
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.
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.
Authors: Georges St Laurent; Dmitry Shtokalo; Michael R Tackett; Zhaoqing Yang; Yuri Vyatkin; Patrice M Milos; Bernd Seilheimer; Timothy A McCaffrey; Philipp Kapranov Journal: Methods Date: 2013-04-04 Impact factor: 3.608
Authors: Anna Gref; Simon K Merid; Olena Gruzieva; Stéphane Ballereau; Allan Becker; Tom Bellander; Anna Bergström; Yohan Bossé; Matteo Bottai; Moira Chan-Yeung; Elaine Fuertes; Despo Ierodiakonou; Ruiwei Jiang; Stéphane Joly; Meaghan Jones; Michael S Kobor; Michal Korek; Anita L Kozyrskyj; Ashish Kumar; Nathanaël Lemonnier; Elaina MacIntyre; Camille Ménard; David Nickle; Ma'en Obeidat; Johann Pellet; Marie Standl; Annika Sääf; Cilla Söderhäll; Carla M T Tiesler; Maarten van den Berge; Judith M Vonk; Hita Vora; Cheng-Jian Xu; Josep M Antó; Charles Auffray; Michael Brauer; Jean Bousquet; Bert Brunekreef; W James Gauderman; Joachim Heinrich; Juha Kere; Gerard H Koppelman; Dirkje Postma; Christopher Carlsten; Göran Pershagen; Erik Melén Journal: Am J Respir Crit Care Med Date: 2017-05-15 Impact factor: 21.405
Authors: Pei-Song Gao; Kenichi Shimizu; Audrey V Grant; Nicholas Rafaels; Lin-Fu Zhou; Sherry A Hudson; Satoshi Konno; Nives Zimmermann; Maria I Araujo; Eduardo V Ponte; Alvaro A Cruz; Masaharu Nishimura; Song-Nan Su; Nobuyuki Hizawa; Terry H Beaty; Rasika A Mathias; Marc E Rothenberg; Kathleen C Barnes; Bruce S Bochner Journal: Eur J Hum Genet Date: 2010-01-20 Impact factor: 4.246
Authors: Miles D Thompson; Valerie Capra; Mark T Clunes; G E Rovati; Jana Stankova; Mary C Maj; David L Duffy Journal: Front Pharmacol Date: 2016-12-01 Impact factor: 5.810
Authors: Manuel A Ferreira; Judith M Vonk; Hansjörg Baurecht; Ingo Marenholz; Chao Tian; Joshua D Hoffman; Quinta Helmer; Annika Tillander; Vilhelmina Ullemar; Jenny van Dongen; Yi Lu; Franz Rüschendorf; Jorge Esparza-Gordillo; Chris W Medway; Edward Mountjoy; Kimberley Burrows; Oliver Hummel; Sarah Grosche; Ben M Brumpton; John S Witte; Jouke-Jan Hottenga; Gonneke Willemsen; Jie Zheng; Elke Rodríguez; Melanie Hotze; Andre Franke; Joana A Revez; Jonathan Beesley; Melanie C Matheson; Shyamali C Dharmage; Lisa M Bain; Lars G Fritsche; Maiken E Gabrielsen; Brunilda Balliu; Jonas B Nielsen; Wei Zhou; Kristian Hveem; Arnulf Langhammer; Oddgeir L Holmen; Mari Løset; Gonçalo R Abecasis; Cristen J Willer; Andreas Arnold; Georg Homuth; Carsten O Schmidt; Philip J Thompson; Nicholas G Martin; David L Duffy; Natalija Novak; Holger Schulz; Stefan Karrasch; Christian Gieger; Konstantin Strauch; Ronald B Melles; David A Hinds; Norbert Hübner; Stephan Weidinger; Patrik K E Magnusson; Rick Jansen; Eric Jorgenson; Young-Ae Lee; Dorret I Boomsma; Catarina Almqvist; Robert Karlsson; Gerard H Koppelman; Lavinia Paternoster Journal: Nat Genet Date: 2017-10-30 Impact factor: 38.330
Authors: Florence Demenais; Patricia Margaritte-Jeannin; Kathleen C Barnes; William O C Cookson; Janine Altmüller; Wei Ang; R Graham Barr; Terri H Beaty; Allan B Becker; John Beilby; Hans Bisgaard; Unnur Steina Bjornsdottir; Eugene Bleecker; Klaus Bønnelykke; Dorret I Boomsma; Emmanuelle Bouzigon; Christopher E Brightling; Myriam Brossard; Guy G Brusselle; Esteban Burchard; Kristin M Burkart; Andrew Bush; Moira Chan-Yeung; Kian Fan Chung; Alexessander Couto Alves; John A Curtin; Adnan Custovic; Denise Daley; Johan C de Jongste; Blanca E Del-Rio-Navarro; Kathleen M Donohue; Liesbeth Duijts; Celeste Eng; Johan G Eriksson; Martin Farrall; Yuliya Fedorova; Bjarke Feenstra; Manuel A Ferreira; Maxim B Freidin; Zofia Gajdos; Jim Gauderman; Ulrike Gehring; Frank Geller; Jon Genuneit; Sina A Gharib; Frank Gilliland; Raquel Granell; Penelope E Graves; Daniel F Gudbjartsson; Tari Haahtela; Susan R Heckbert; Dick Heederik; Joachim Heinrich; Markku Heliövaara; John Henderson; Blanca E Himes; Hiroshi Hirose; Joel N Hirschhorn; Albert Hofman; Patrick Holt; Jouke Hottenga; Thomas J Hudson; Jennie Hui; Medea Imboden; Vladimir Ivanov; Vincent W V Jaddoe; Alan James; Christer Janson; Marjo-Riitta Jarvelin; Deborah Jarvis; Graham Jones; Ingileif Jonsdottir; Pekka Jousilahti; Michael Kabesch; Mika Kähönen; David B Kantor; Alexandra S Karunas; Elza Khusnutdinova; Gerard H Koppelman; Anita L Kozyrskyj; Eskil Kreiner; Michiaki Kubo; Rajesh Kumar; Ashish Kumar; Mikko Kuokkanen; Lies Lahousse; Tarja Laitinen; Catherine Laprise; Mark Lathrop; Susanne Lau; Young-Ae Lee; Terho Lehtimäki; Sébastien Letort; Albert M Levin; Guo Li; Liming Liang; Laura R Loehr; Stephanie J London; Daan W Loth; Ani Manichaikul; Ingo Marenholz; Fernando J Martinez; Melanie C Matheson; Rasika A Mathias; Kenji Matsumoto; Hamdi Mbarek; Wendy L McArdle; Mads Melbye; Erik Melén; Deborah Meyers; Sven Michel; Hamida Mohamdi; Arthur W Musk; Rachel A Myers; Maartje A E Nieuwenhuis; Emiko Noguchi; George T O'Connor; Ludmila M Ogorodova; Cameron D Palmer; Aarno Palotie; Julie E Park; Craig E Pennell; Göran Pershagen; Alexey Polonikov; Dirkje S Postma; Nicole Probst-Hensch; Valery P Puzyrev; Benjamin A Raby; Olli T Raitakari; Adaikalavan Ramasamy; Stephen S Rich; Colin F Robertson; Isabelle Romieu; Muhammad T Salam; Veikko Salomaa; Vivi Schlünssen; Robert Scott; Polina A Selivanova; Torben Sigsgaard; Angela Simpson; Valérie Siroux; Lewis J Smith; Maria Solodilova; Marie Standl; Kari Stefansson; David P Strachan; Bruno H Stricker; Atsushi Takahashi; Philip J Thompson; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Carla M T Tiesler; Dara G Torgerson; Tatsuhiko Tsunoda; André G Uitterlinden; Ralf J P van der Valk; Amaury Vaysse; Sailaja Vedantam; Andrea von Berg; Erika von Mutius; Judith M Vonk; Johannes Waage; Nick J Wareham; Scott T Weiss; Wendy B White; Magnus Wickman; Elisabeth Widén; Gonneke Willemsen; L Keoki Williams; Inge M Wouters; James J Yang; Jing Hua Zhao; Miriam F Moffatt; Carole Ober; Dan L Nicolae Journal: Nat Genet Date: 2017-12-22 Impact factor: 38.330
Authors: Cheng-Jian Xu; Olena Gruzieva; Cancan Qi; Ana Esplugues; Ulrike Gehring; Anna Bergström; Dan Mason; Leda Chatzi; Daniela Porta; Karin C Lodrup Carlsen; Nour Baïz; Anne-Marie Madore; Harri Alenius; Bianca van Rijkom; Soesma A Jankipersadsing; Pieter van der Vlies; Inger Kull; Marianne van Hage; Mariona Bustamante; Aitana Lertxundi; Matias Torrent; Gillian Santorelli; Maria Pia Fantini; Vegard Hovland; Giancarlo Pesce; Nanna Fyhrquist; Tiina Laatikainen; Martijn C Nawijn; Yang Li; Cisca Wijmenga; Mihai G Netea; Jean Bousquet; Josep M Anto; Catherine Laprise; Tari Haahtela; Isabella Annesi-Maesano; Kai-Håkon Carlsen; Davide Gori; Manolis Kogevinas; John Wright; Cilla Söderhäll; Judith M Vonk; Jordi Sunyer; Erik Melén; Gerard H Koppelman Journal: J Allergy Clin Immunol Date: 2020-12-15 Impact factor: 10.793
Authors: Anu Laulajainen-Hongisto; Annina Lyly; Paula Kauppi; Sanna Toppila-Salmi; Tanzeela Hanif; Kishor Dhaygude; Matti Kankainen; Risto Renkonen; Kati Donner; Pirkko Mattila; Tuomas Jartti; Jean Bousquet Journal: Clin Transl Allergy Date: 2020-10-28 Impact factor: 5.871
Authors: Sigurveig T Sigurdardottir; Kristjan Jonasson; Michael Clausen; Kristin Lilja Bjornsdottir; Sigridur Erla Sigurdardottir; Graham Roberts; Kate Grimshaw; Nikolaos G Papadopoulos; Paraskevi Xepapadaki; Ana Fiandor; Santiago Quirce; Aline B Sprikkelman; Lies Hulshof; Marek L Kowalski; Marcin Kurowski; Ruta Dubakiene; Odilija Rudzeviciene; Johanna Bellach; Songül Yürek; Andreas Reich; Sina Maria Erhard; Philip Couch; Montserrat Fernandez Rivas; Ronald van Ree; Clare Mills; Linus Grabenhenrich; Kirsten Beyer; Thomas Keil Journal: Allergy Date: 2021-06-08 Impact factor: 14.710
Authors: Aljuaid Eidha Fawzan; Sara Ahmad Assiri; Raad M M Althaqafi; Atheer Alsufyani; Ahmad Saeed A Alghamdi Journal: World J Otorhinolaryngol Head Neck Surg Date: 2022-05-04