LSC Abstract – Systems approach to predict asthmatic response to allergen inhalation challenge

Abstract

Individuals with allergic asthma respond differently, but reproducibly, to allergen inhalation challenge (AIC). Some individuals develop an isolated early response (early responders, ERs) while others also go on to develop a late response (dual responders, DRs). Since new drugs for allergic asthma are targeted towards attenuating the late phase response, we sought to identify a multi-omic biomarker panel that can screen mild asthmatics for those likely to exhibit the late response. 32 individuals participated: 15 (17) were classified as ERs (DRs), respectively. Blood samples were collected prior to the AIC. Measurements of cell counts were obtained using a hematolyzer; gene transcript relative levels using RNA sequencing; metabolite levels using tandem mass spectrometry. Sparse generalized canonical correlation discriminant analysis was used to classify ERs and DRs by integrating all three datasets adjusting for age, sex and allergen. Geneset enrichment analysis was performed using Enrichr. We developed a multi-signature classifier consisting of 2 cell types, 10 gene transcripts and 10 metabolites, with an error rate of 20±8.3% (10x5-fold cross-validation). The cells selected in the multi-signature panel included lymphocytes and monocytes. The selected metabolites were enriched for phosphatidylcholines. The top 10 enriched pathways in the selected gene transcripts included the phosphatidylinositol signalling system. In summary, molecular signatures in blood may have utility to screen for asthmatic individuals who develop the late asthmatic response following AIC. This study implicates the arachidonic acid metabolism pathway in leading to the early or late phase asthmatic response.