Introduction: Asthma represents heterogeneous collection of diseases. Therefore, an improved understanding of pathogenetically distinct subtypes (i.e. endotypes) could help to tailor clinical interventions within established asthma cases according to the endotypes. Objective: to identify key biological endotypes of childhood asthma severity, considering ambient polycyclic aromatic hydrocarbon (PAH) concentrations during childhood. Methods: During the year 2008-2010, an integrative genomics investigation was conducted with asthma cases (n=200) and controls (n=200) residing in Czech Republic. Multi-axial pathways of asthma analyses were conducted by considering ambient air pollution, genotype, epigenetic modulation, gene expression, and oxidative damage data. Results: Global Bayesian network, constructed by integrating gene expression data of asthmatic children with transcription factor target information, revealed the genes within interferon response (p=1e-40, 5-fold) and TNF-alpha signaling (p=1.6e-08, 2.7 fold) as the key pathogenetic mechanism of asthma within high air pollution region. The key driver genes of the primary module include TLR6, IL1RN, NAMPT, and FPR2. The second most robust module is enriched for oxidative phosphorylation (p=8e-10, 8.6 fold) and ribosome (p=1.5e-09, 9.2 fold) pathway. Specifically, C17orf61, RPS14, RPAIN, BOLA2 and SNRPF represent the top key driver genes of this module. Furthermore, top key driver gene, TLR6, in interferon response module was significantly associated with BOLA2 gene within oxidative phosphorylation module. Conclusion: The genes within interferon response and TNF-alpha signaling coexpression subnetworks are enriched in children with severe asthma. These genes have been functionally validated for their roles early childhood asthma inflammation, lung inflammatory responses, and allergic reactions.