Nasal transcriptome differences preceding recurrent wheezing in infancy.

Background: Mucosal immune responses and epithelial barrier function are key emerging determinants of susceptibility to wheezing illnesses in early life.

Objective: We investigated the association between nasal transcriptome in healthy infants and the subsequent incidence of recurrent wheeze.

Methods: In a population-derived prebirth cohort study, whole transcriptome sequencing was performed to compare the nasal transcriptome at 1 month of age from 26 infants who subsequently developed recurrent wheeze (parents' record in symptom diary) in the first year of life to 22 infants who remained recurrent wheeze-free. Differentially expressed genes (DEGs) were identified using DEseq2, followed by over-representation pathway (GO and KEGG) and upstream regulator analyses (Ingenuity Pathway Analysis).

Results: 202 DEGs (false discovery rate ≤ 0.1 and absolute log₂ fold change > 1; 66 upregulated and 136 downregulated) were associated with recurrent wheeze. Upregulated GO pathways associated with recurrent wheeze included chemokine-mediated signalling, eosinophil and monocyte chemotaxis. The downregulated GO included cilium organisation and cellular aldehyde metabolic process. TNF emerged as the key driver (adjusted p-value and Z-score) of DEG patterns in the recurrent wheeze group, with OSMR and IL21 identified as master regulators.

Conclusion: The nasal transcriptome in early infancy is associated with subsequent recurrent wheezes, indicating upregulation of immune cell chemotaxis, decreased epithelial barrier function, and altered cilium organisation and mitochondrial function. Future studies are required to evaluate the use of nasal transcriptome in the early detection of infants at risk of recurrent wheeze and to generate new knowledge of antecedent pathways as targets for novel primary prevention strategies.