Transcriptomics highlight eosinophils and TH2 as disease-driving
cells in AR
We assessed whole blood gene expression comparing AR and non-AR
individuals from our previously described SSIC cohort using whole
transcriptomic sequencing (Supplementary Table 2A ). A total of
1160 unique probes associated to 1095 unique genes were differentially
expressed at a nominal significance level of 0.05. A total of 23 probes
representing 20 unique gene transcripts were robust after stringent
correction for multiple testing at a false discovery rate (FDR) p-value
of 0.05, with all transcripts upregulated in AR (Table 1A ).
Given that atopy is well known to be associated with eosinophil levels,
sensitivity analysis with adjustment for eosinophil counts was
performed, with all identified differentially expressed genes (DEGs)
remaining significant post adjustment. To account for ethnicity and
environmental influences on atopic gene expression, we validated our
findings in BAMSE population-based cohort comprising of Swedish
adolescents (Table 1B ). Out of 20 DEGs identified in the SSIC
cohort, 11 DEGs were replicated and reached significance in BAMSE,
confirming the transferability of our findings irrespective of ethnicity
and environmental differences (Table 1B ).
For top DEGs that reached nominal significance in the SSIC cohort, we
interrogated for biological function and performed Ingenuity Pathway
Analysis (IPA). In the disease and disorders category, hypersensitivity
and inflammatory responses were significantly associated with nominal
AR-related DEGs (Table 2A ). Top pathways enriched for
hypersensitivity and inflammatory responses included cell-to-cell
signalling and haematological system and cell-mediated immune response
(Table 2B, C ). Importantly, we observed strong functional
enrichment for eosinophils, along with basophils and mast cells, in
hypersensitivity responses associated with AR (Table 2B ).
Similarly, functional activation of TH2 and myeloid cells were
highlighted to drive inflammatory responses in AR (Table 2C) .
Consistent with current understanding, transcriptomic findings emphasise
eosinophils and TH2 cells as key drivers of AR.