Differential gene expression profile in PBMCs from subjects with AERD and ATA: a gene marker for AERD

Abstract

Aspirin-exacerbated respiratory disease (AERD) is associated with severe asthma and aspirin can cause asthma to worsen, often in the form of a severe and sudden attack. The oral aspirin challenge is the gold standard to confirm the diagnosis of AERD, but it is time consuming and produces serious complications in some cases. Therefore, more efficient and practical method is needed to predict AERD patients. The aim of the present study was to identify AERD-related gene expression in peripheral blood mononuclear cells (PBMCs) and examine the diagnostic potential of these candidate gene(s) for predicting AERD. To do this, RNAs from 24 subjects with AERD and 18 subjects with aspirin-tolerant asthma (ATA) were subjected to microarray analysis of ~34,560 genes. In total, 10 genes were selected as candidate gene markers by applying p ≤ 0.001(t test) and ≥8-fold change, and to correct for multiple comparisons, the false discovery rate analyses were performed. By applying multiple logistic regression analysis, among possible 1,023 models (2(10)-1), a model consisting of CNKSR3, SPTBN2, and IMPACT was selected as candidate set, because this set showed the best AUC (0.98) with 88 % sensitivity and 89 % specificity. For validation, mRNA levels by real-time PCR on PBMCs from two population sets in a gene-chip study and another replication sample, 20 AERD, 20 ATA, and 8 normal controls, were significantly different between groups with 100 % sensitivity and 100 % specificity in each of the two population sets. However, IMPACT gene did not differentiate between AERD and normal controls. The set of the two genes (CNKSR3 and SPTBN2) showed the best AUC (0.96) with 88 % sensitivity and 94 % specificity in a gene-chip study sample. In addition, this set showed perfect discriminative power with AUC (1.0, 100 % sensitivity and 100 % specificity) in each of the two population sets: the gene-chip samples and the replication samples. It also showed perfect discrimination for AERD from NC (AUC: 1.0) and ATA from NC (AUC: 1.0). In conclusion, we developed the two gene markers (CNKSR3 and SPTBN2) of PBMC which differentiate between AERD and ATA with a perfect discriminative power. These gene markers may be an efficient and practical method for predicting AERD.

DNA Methylation Profiles of Airway Epithelial Cells and PBMCs from Healthy, Atopic and Asthmatic Children

“…We also identified 8 genes with differentially methylated CpG sites in AECs derived from asthmatic compared to AECs obtained from atopic children. Although gene markers in PBMCs have been identified through gene expression analysis for multiple diseases including aspirin-exacerbated respiratory disease and asthma [35], [36], we did not identify any differences in DNA methylation when comparing PBMCs from the three subject groups.…”

The Genetics of Drug Hypersensitivity Reactions

“…Deep sequencing studies can also be performed. In this sense, a recent genome-wide methylation study on nasal polyps found a differential pattern in patients with NSAID-induced DHRs [133], and a set of 2 gene markers has been proposed to discriminate NERD from aspirin-tolerant asthma [134]. Exome sequencing has also been used to identify variants associated with hypersensitivity to NSAIDs [135].…”

Integrative information theoretic network analysis for genome-wide association study of aspirin exacerbated respiratory disease in Korean population

“…Administration of annexin protein prior to an ovalbumin challenge significantly reduced airway hyperresponsiveness, attenuated the production of inflammatory cytokines, such as IL-4, IL-5, and IL-13, as well as ovalbumin-specific IgE in a mouse model of asthma [48]. Meanwhile, neuroactive ligand-receptor interaction, which is another enriched pathway, was reported as a significantly enriched pathway in a differential gene expression study with AERD and ATA subjects [49]. Therefore, we suppose the major modules in the integrated network can play an important role in the pathways related to the treatment of AERD.…”