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

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.

Allergic rhinitis

“…Indeed, data from genome-wide association studies (GWAS) have demonstrated that allergic diseases and traits share a large number of genetic susceptibility loci, of which IL33, IL1RL1 (also known as IL33R), IL13-RAD50, C11orf30 (also known as EMSY)-LRRC32 and TSLP seem to be important for multimorbid allergic diseases 18,23 . In addition, rhinitis was associated with TLR expression, whereas AR associated with asthma was associated with IL5 and IL33, suggesting a different genetic cause for AR alone compared with multimorbid AR 24 . Further research is warranted to explore transcriptomic signatures as biomarkers for single and multimorbid allergic diseases.…”

“…In addition, there are probably common genes associated with asthma and AR and specific genes associated with AR alone. Combining big data analyses (such as from the MASK-air application 135 ), classical epidemiological studies, in silico analysis, transcriptomics using microarray data (as exemplified in MeDALL 22,24,35 ) or RNA sequencing 176 has led to the reclassification of the mechanisms of allergic diseases. For example, polysensitization and multimorbidity represent the extreme allergic phenotype, starting early in life, and are associated with IL5 and IL33 activation.…”

Efficacy and safety of dupilumab for moderate-to-severe atopic dermatitis: a systematic review for the EAACI Biologicals Guidelines

“…AD displays a highly complex pathophysiology and heterogeneous phenotypes, which are illustrated by different features such as age of disease onset, variable response to triggers, spectrum of severity, barrier defect, potential of IgE autoreactivity and comorbidities (asthma, rhinitis, food allergy and infections) (1,2,3,4,5,6). Similar to asthma, AD research is developing and shaping precision medicine approaches aiming towards a biomarker based molecular taxonomy (7,8,9,10).…”

Single‑nucleotide polymorphisms and haplotypes in the interleukin‑33 gene are associated with a risk of allergic rhinitis in the Chinese population

“…Therefore, it is of interest to examine the association between the GWAS risk loci of asthma and AR. IL-33 has been highlighted as an important initiating factor for allergic asthma, and a recent study on whole blood gene expression profiles has revealed a consistent overexpression of the IL1RL1 gene, which encodes IL-33 receptor ST2, in patients diagnosed with multiple morbidities for asthma, dermatitis and rhinitis compared with normal controls (68). Therefore, the present study aimed to explore whether polymorphisms in IL-33 also affect the susceptibility to AR.…”