The whole - genome expression analysis of peripheral blood mononuclear cells from aspirin sensitive asthmatics versus aspirin tolerant patients and healthy donors after in vitro aspirin challenge

Abstract

BackgroundUp to 30 % of adults with severe asthma are hypersensitive to aspirin and no unambiguous theory exists which provides a satisfactory explanation for the occurrence of aspirin-induced asthma (AIA) in some asthmatic patients. Therefore, the aim of this study was to compare the AIA expression profile against aspirin tolerant asthma (ATA) and healthy volunteers (HV) profile in peripheral blood mononuclear cells (PBMCs) after in vitro aspirin challenge in Caucasian population.MethodsPBMCs were separated from blood of three groups of subjects - 11 AIA, 7 ATA and 15 HV and then stimulated by either 2 μM lysine aspirin or 20 μM lysine as a control. Subsequently, RNA was isolated, transcribed into cDNA and subjected to microarray and qPCR studies. Simultaneously, protein was extracted from PBMCs and used in further immunoblotting analysis.ResultsThe validation of results at mRNA level has shown only three genes, whose expression was significantly altered between comprising groups. mRNA expression of CNPY3 in PBMCs in AIA was significantly lower (-0.41 ± 2.67) than in HV (1.04 ± 2.69), (p = 0.02); mRNA expression of FOSL1 in PBMCs in AIA was also significantly decreased (-0.66 ± 2.97) as opposed to HV (0.31 ± 4.83), (p = 0.02). While mRNA expression of ERAS in PBMCs was increased (1.15 ± 0.23) in AIA in comparison to HV (-1.32 ± 0.41), (p = 0.03). At protein level the changed expression of one protein was confirmed. Protein expression of FOSL1 in PBMCs in AIA was both significantly lower (-0.86 ± 0.08) than in ATA (0.39 ± 0.42), (p = 0.046) and in HV (0.9 ± 0.27), (p = 0.007).ConclusionsThis pilot study implies a positive association between CNPY3, ERAS, FOSL1 and aspirin-intolerant asthma, suggesting that these findings would be useful for further investigations of NSAIDs mechanism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0305-4) contains supplementary material, which is available to authorized users.

Genetic and Epigenetic Components of Aspirin-Exacerbated Respiratory Disease

“…In particular, expression of CNPY3 and FOSL1 were significantly lower in AIA vs healthy controls, while ERAS expression was increased. Protein expression of FOSL1 in PBMCs was also significantly lower for AIA than the control groups 75 . While the study lacked mechanistic investigation of these novel candidate genes for AERD, the authors suggest these genes could participate in innate immune response pathways and pathways for tissue/cell remodeling and airway hyperresponsiveness that contribute to the pathogenesis of AERD 75 .…”

“…Comparing gene expression and whole genome sequence profiles from AERD cases and non-AERD asthmatics or healthy controls using whole-genome microarray expression profiling and next-generation sequencing methods provides a discovery-based approach to interrogate mRNA transcripts across the genome with specific correlation to the phenotype. A combined approach utilizing microarray expression profiling and a candidate gene analysis in PBMCs from a small Caucasian population identified three genes with expression profiles that significantly differed between AIA vs. ATA and/or AIA vs. healthy subjects 75 . In particular, expression of CNPY3 and FOSL1 were significantly lower in AIA vs healthy controls, while ERAS expression was increased.…”

Identification of key genes and pathways between mild-moderate and severe asthmatics via bioinformatics analysis

“…Through transcriptome-wide association studies, transcription factor RERE was identified as a candidate causal gene of asthma 41 . The whole-genome expression analysis of peripheral blood mononuclear cells indicated that FOSL1 was positively associated with aspirin-intolerant asthma 42 . In addition, miR-20a epigenetically regulated the IL-10 production by targeting HDAC4 and attenuated allergic inflammation in the human mast cells.…”

Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts

“…As part of the FOSL1/AP-1 transcription factor, it regulates gene expression in human lung epithelia ( Elangovan et al, 2018 ). mRNA expression of FOSL1 was shown to be decreased in PBMCs of aspirin-intolerant asthma ( Kacprzak et al, 2014 ; Wieczfinska et al, 2015 ).…”