Interactomics-based analysis suggests that rhinitis and rhinitis with asthma are mechanistically different diseases

In a recent article published in Scientific Reports, researchers used human transcriptomic data from the Mechanisms of the Development of Allergy (MeDALL) study to differentiate the molecular mechanisms associated with two phenotypes of allergic rhinitis: rhinitis alone (R) and rhinitis in multimorbidity with asthma (R+A).

Distinction between rhinitis alone and rhinitis with asthma using interactomics
Study: Distinction between rhinitis alone and rhinitis with asthma using interactomics. Image Credit: Budimir Jevtic/Shutterstock.com

Background

Rhinitis alone affects nearly 70–80% of patients with allergic rhinitis (R). However, it clusters with asthma (A) in multimorbidity to affect 20–30% of patients. Conversely, the majority of patients with asthma had or still have rhinitis. 

There are genetic, clinical, and immunological differences between monosensitization (one allergen) and polysensitization (multiple allergens). This raises the possibility of distinct molecular pathways in R + A and R. Consequently, the 20-year-old concept of “one-airway-one-disease” might not hold true.

Previous efforts to comprehend the connections between R and R+A have included using the atopic march sequence and characterizing the molecular mechanisms governing these diseases and the interactions between them.

Interactomics, a branch of systems biology, applies biostatistical methodologies and data mining to provide a molecular context to the cell behavior and functions under different physiological conditions, including pathological ones, and facilitate an understanding of the complexity of many phenotypes.

About the study

In the present study, researchers used whole blood samples from three birth cohorts from Sweden, Spain and Germany from the MeDALL study. Next, they applied an interactomics approach to characterize the molecular pathways associated with R and R + A, including obtaining data on differentially expressed genes (DEGs).

The team used the IntAct database to independently generate the interactomes of the DEGs for R and R + A that comprised >106 protein–protein interactions in human cells. 

Similarly, they used the DAVID web-based tool to annotate these interactomes functionally. They considered molecular pathways in levels 3 and 4 (intermediate) of the Reactome database hierarchy. Furthermore, they assigned each molecular pathway to a generic functional family.

Results

Of the 786 study participants, 45%, 42%, and 51% had asthma, dermatitis, and rhinitis, respectively. Of those with asthma, 61% had this condition with multimorbidity. Of all three cohorts, BAMSE had the most asthma patients (63%).

Topological analysis of interactomes revealed that the R interactome had 464 genes connected by 466 edges, while the R+A interactome had 130 genes connected by 149 edges. 

Random distributions testing the degree of interconnectedness of the interactomes showed that the interactomes of R and R+A were denser than random expectation (2.18 and 6.22 times denser, respectively) and also statistically significant with z-test; P = 1.09x10–11 and 3.42x10–50.
Intriguingly, 25 genes were common to both interactomes, implying a degree of interconnectedness larger than random expectation.

Functional annotation revealed that several pathways were specific to R, including but not limited to toll-like receptor (TLR) signaling cascades and WNT5A-dependent signaling. 
Signal-transduction-related processes were more represented in pathways specific to R + A. 

Interleukin (IL)-33-mediated signaling stood out as a pathway specific to R + A. IL-33 is an alarmin cytokine with a critical role in inflammation, allergy, and type 2 immunity. 

The authors also noted increased fibroblast growth factor receptor (FGFR) signaling in the R + A phenotype. Besides playing important roles in embryogenesis, angiogenesis, wound repair, and lung development, this signaling system is relevant in A remodeling.

Conclusions

The study analysis showed high connectivity within the interactomes of R and R+A, but a lack of common DEGs. Despite having some core common mechanisms, the two R phenotypes were significantly different. 

Differences were seen in the molecular pathways specific to R (SUMO pathways, MyD88 and TLR signaling cascades) and R + A (FGFR-mediated signaling, IL-33-mediated signaling).

Together these findings indicate that rhinitis alone and rhinitis in comorbidity with asthma are mechanistically different diseases with varying underlying molecular pathways. This data could help refine the MeDALL hypothesis on allergic diseases.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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