Functional genomics of the peripheral blood response to allergen inhalation challenge

Objective/purposeIn asthmatic individuals, airway narrowing representsthe early phase of the asthmatic response to allergeninhalation challenge, occurring within thirty minutes [1].In 50-60% of allergic asthmatic adults, the earlyresponse is followed by the late phase asthmaticresponse, usually starting between 3-4 hours after aller-gen inhalation challenge [2], and characterized mainlyby cellular inflammation of the airway [3]. The pathwaysleading to the late response are not completely under-stood. Understanding these pathways is important forevaluating allergic diseases such as asthma. In contrastto the more transient isolated early response, develop-ment of the late response is associated with the hall-mark inflammatory features of chronic allergic disease.MethodsNine adult subjects participating in ethically approvedallergen challenge studies were recruited followinginformed consent. Inclusion criteria included non-smo-kers with stable, mild to moderate atopic asthma, free ofother lung diseases. Subjects developing either an iso-lated early asthmatic response (≥20% drop in FEV1within 2 hours) or the dual asthmatic response (earlyresponse + ≥15% drop in FEV1 between 3-7 hours)were studied. Peripheral blood was drawn just prior toinhalation challenge and 2-3 hours post-challenge. Geneexpression analysis was performed using AffymetrixGeneChip® microarrays.Findings1783 genes were differentially expressed between pre-and post-inhalation challenge (p≤ 0.01). 364 genesremained significant at an FDR of 10%. Within this set,the DNAJC1 gene (p = 7.2e-5) has been previously iden-tified in a GWAS (genome-wide association study) asassociated with asthma. Gene ontology showed per-turbed activity in immune system process, mast cellsecretory granules and immunoglobulin biosynthesis.DeliverablesThe peripheral blood transcriptome was perturbedbetween pre-allergen inhalation challenge and 2-3 hourspost-challenge, with a focus on immunological func-tions. DNAJC1 was identified to be a gene for possiblefurther investigation. Additional recruitment of subjectsis underway to identify more specific biological path-ways that may be relevant to the onset of the late asth-matic response.RelevanceThis research will act as an initial step in identifyinggenes and pathways that may be involved in the moreclinically severe late asthmatic response that follows theearly response in more than half of the asthmatic popu-lation. The discovery of these biological pathways willallow for a better understanding of why some indivi-duals develop a dual response instead of an isolatedearly response. It will also indicate potential therapeutictargets that can be utilized to minimize the late asth-matic response, leading to better treatments for peoplewith asthma and other allergies.