A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents

Nathanaël Lemonnier, Erik Melén, Yale Jiang, Stéphane Joly, Camille Ménard, Daniel Aguilar, Edna Acosta-Perez, Anna Bergström, Nadia Boutaoui, Mariona Bustamante, Glorisa Canino, Erick Forno, Juan Ramon González, Judith Garcia-Aymerich, Olena Gruzieva, Stefano Guerra, Joachim Heinrich, Inger Kull, Jesús Ibarluzea Maurolagoitia, Loreto Santa-Marina RodriguezElisabeth Thiering, Magnus Wickman, Cezmi Akdis, Mübeccel Akdis, Wei Chen, Thomas Keil, Gerard H. Koppelman, Valérie Siroux, Cheng Jian Xu, Pierre Hainaut, Marie Standl, Jordi Sunyer, Juan C. Celedón, Josep Maria Antó, Jean Bousquet

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3248-3260
Number of pages13
JournalAllergy: European Journal of Allergy and Clinical Immunology
Issue number12
StatePublished - Dec 2020


  • asthma
  • atopic dermatitis
  • multimorbidity
  • rhinitis
  • transcriptomics

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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