Integrated study of systemic and local airway transcriptomes in asthma reveals causal mediation of systemic effects by airway key drivers

Abstract Background Systemic and local profiles have each been associated with asthma, but parsing causal relationships between system-wide and airway-specific processes can be challenging. We sought to investigate systemic and airway processes in asthma and their causal relationships. Methods Three hundred forty-one participants with persistent asthma and non-asthmatic controls were recruited and underwent peripheral blood mononuclear cell (PBMC) collection and nasal brushing. Transcriptome-wide RNA sequencing of the PBMC and nasal samples and a series of analyses were then performed using a discovery and independent test set approach at each step to ensure rigor. Analytic steps included differential expression analyses, coexpression and probabilistic causal (Bayesian) network constructions, key driver analyses, and causal mediation models. Results Among the 341 participants, the median age was 13 years (IQR = 10–16), 164 (48%) were female, and 200 (58.7%) had persistent asthma with mean Asthma Control Test (ACT) score 16.6 (SD = 4.2). PBMC genes associated with asthma were enriched in co-expression modules for NK cell-mediated cytotoxicity (fold enrichment = 4.5, FDR = 6.47 × 10 −32 ) and interleukin production (fold enrichment = 2.0, FDR = 1.01 × 10 −15 ). Probabilistic causal network and key driver analyses identified NK cell granule protein ( NKG7 , fold change = 22.7, FDR = 1.02 × 10 −31 ) and perforin ( PRF1 , fold change = 14.9, FDR = 1.31 × 10 −22 ) as key drivers predicted to causally regulate PBMC asthma modules. Nasal genes associated with asthma were enriched in the tricarboxylic acid (TCA) cycle module (fold enrichment = 7.5 FDR = 5.09 × 10 −107 ), with network analyses identifying G3BP stress granule assembly factor 1 ( G3BP1 , fold change = 9.1 FDR = 2.77 × 10 −5 ) and InaD-like protein ( INADL , fold change = 5.3 FDR = 2.98 × 10 −9 ) as nasal key drivers. Causal mediation analyses revealed that associations between PBMC key drivers and asthma are causally mediated by nasal key drivers (FDR = 0.0076 to 0.015). Conclusions Integrated study of the systemic and airway transcriptomes in a well-phenotyped asthma cohort identified causal key drivers of asthma among PBMC and nasal transcripts. Associations between PBMC key drivers and asthma are causally mediated by nasal key drivers.