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

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.