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Aspirin-exacerbated respiratory disease (AERD) is characterized by asthma, tissue eosinophilia, overproduction of cysteinyl leukotrienes (cysLTs), and respiratory reactions to nonselective cyclooxygenase (COX) inhibitors. Ex vivo studies suggest that functional abnormalities of the COX-2/microsomal prostaglandin (PG)E ₂ synthase-1 system may underlie AERD. We demonstrate that microsomal PGE ₂ synthase-1 null mice develop a remarkably AERD-like phenotype in a model of eosinophilic pulmonary inflammation. Lysine aspirin (Lys-ASA)–challenged PGE ₂ synthase-1 null mice exhibit sustained increases in airway resistance, along with lung mast cell (MC) activation and cysLT overproduction. A stable PGE ₂ analog and a selective E prostanoid (EP) ₂ receptor agonist blocked the responses to Lys-ASA by ∼90%; EP ₃ and EP ₄ agonists were also active. The increases in airway resistance and MC products were blocked by antagonists of the type 1 cysLT receptor or 5-lipoxygenase, implying that bronchoconstriction and MC activation were both cysLT dependent. Lys-ASA–induced cysLT generation and MC activation depended on platelet-adherent granulocytes and T-prostanoid (TP) receptors. Thus, lesions that impair the inducible generation of PGE ₂ remove control of platelet/granulocyte interactions and TP-receptor–dependent cysLT production, permitting MC activation in response to COX-1 inhibition. The findings suggest applications of antiplatelet drugs or TP receptor antagonists for the treatment of AERD.

Aspirin-exacerbated respiratory disease (AERD) is a nonallergic clinical syndrome characterized by a severe decline in forced expiratory volume in one second (FEV1) following the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin. The effects of genetic variants have not fully explained all of the observed individual differences to an aspirin challenge despite previous attempts to identify AERD-related genes. In the present study, we performed genome-wide association study (GWAS) and targeted association study in Korean asthmatics to identify new genetic factors associated with AERD. A total of 685 asthmatic patients without AERD and 117 subjects with AERD were used for the GWAS of the first stage, and 996 asthmatics without AERD and 142 subjects with AERD were used for a follow-up study. A total of 702 SNPs were genotyped using the GoldenGate assay with the VeraCode microbead. GWAS revealed the top-ranked variants in 3′ regions of the HLA-DPB1 gene. To investigate the detailed genetic effects of an associated region with the risk of AERD, a follow-up targeted association study with the 702 single nucleotide polymorphisms (SNPs) of 14 genes was performed on 802 Korean subjects. In a case–control analysis, HLA-DPB1 rs1042151 (Met105Val) shows the most significant association with the susceptibility of AERD ( p  = 5.11 × 10 −7 ; OR = 2.40). Moreover, rs1042151 also shows a gene dose for the percent decline of FEV1 after an aspirin challenge ( p  = 2.82 × 10 −7 ). Our findings show that the HLA-DPB1 gene polymorphism may be the most susceptible genetic factor for the risk of AERD in Korean asthmatics and confirm the importance of HLA-DPB1 in the genetic etiology of AERD.

Cysteinyl leukotriene (cysLT) overproduction and eosinophil activation are hallmarks of aspirin-exacerbated respiratory disease (AERD). However, pathogenic mechanisms of AERD remain to be clarified. Here, we aimed to find the significance of transforming growth factor beta 1 (TGF-β1) in association with cysteinyl leukotriene E 4 (LTE 4 ) production, leading to eosinophil degranulation. To evaluate levels of serum TGF-β1, first cohort enrolled AERD (n = 336), ATA (n = 442) patients and healthy control subjects (HCs, n = 253). In addition, second cohort recruited AERD (n = 34) and ATA (n = 25) patients to investigate a relation between levels of serum TGF-β1 and urinary LTE 4 . The function of TGF-β1 in LTE 4 production was further demonstrated by ex vivo (human peripheral eosinophils) or in vivo (BALB/c mice) experiment. As a result, the levels of serum TGF-β1 were significantly higher in AERD patients than in ATA patients or HCs ( P = .001; respectively). Moreover, levels of serum TGF-β1 and urinary LTE 4 had a positive correlation ( r = 0.273, P = .037). In the presence of TGF-β1, leukotriene C 4 synthase (LTC 4 S) expression was enhanced in peripheral eosinophils to produce LTE 4 , which sequentially induced eosinophil degranulation via the p38 pathway. When mice were treated with TGF-β1, significantly induced eosinophilia with increased LTE 4 production in the lung tissues were noted. These findings suggest that higher levels of TGF-β1 in AERD patients may contribute to LTE 4 production via enhancing LTC 4 S expression which induces eosinophil degranulation, accelerating airway inflammation.

Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E2 (PGE2), which elicits antiproliferative effects mediated through the E prostanoid (EP)2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE2 and a selective EP2 agonist (P < 0.0001 at 1 μM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P < 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP4, and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP2 promoter correlated strongly with baseline EP2 mRNA (r = 0.80; P < 0.01). These studies suggest that the EP2 promotor is under epigenetic control, and one explanation for PGE2 resistance in AERD is an epigenetically mediated reduction of EP2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome.

Chronic rhinosinusitis with nasal polyps is affecting up to 3% of Western populations. About 10% of patients with nasal polyps also suffer from asthma and intolerance to aspirin, a syndrome called aspirin-exacerbated respiratory disease. Although eosinophilic inflammation is predominant in polyps of both diseases, phenotypic differences in the tissue-derived microenvironment, elucidating disease-specific characteristics, have not yet been identified. We sought to obtain detailed information about phenotypic and transcriptional differences in epithelial and immune cells in polyps of aspirin-tolerant and intolerant patients. Cytokine profiles in nasal secretions and serum of patients suffering from aspirin-exacerbated respiratory disease (n = 10) or chronic rhinosinusitis with nasal polyps (n = 9) were assessed using a multiplex mesoscale discovery assay. After enrichment for immune cell subsets by flow cytometry, we performed transcriptomic profiling by employing single-cell RNA sequencing. Aspirin-intolerant patients displayed significantly elevated IL-5 and CCL17 levels in nasal secretions corresponding to a more pronounced eosinophilic type 2 inflammation. Transcriptomic profiling revealed that epithelial and mast cells not only complement one another in terms of gene expression associated with the 15-lipoxygenase pathway but also show a clear type 2-associated inflammatory phenotype as identified by the upregulation of POSTN , CCL26 , and IL13 in patients with aspirin-exacerbated respiratory disease. Interestingly, we also observed cellular stress responses indicated by an increase of MTRNR2L12 , MTRNR2L8 , and NEAT1 across all immune cell subsets in this disease entity. In conclusion, our findings support the hypothesis that epithelial and mast cells act in concert as potential drivers of the pathogenesis of the aspirin-exacerbated respiratory disease.

Patients with aspirin-exacerbated respiratory disease (AERD) are known to have poor clinical outcomes. The pathogenic mechanisms have not yet been completely understood. We aimed to assess the involvement of the de-novo synthetic pathway of sphingolipid metabolism in patients with AERD compared to those with aspirin tolerant asthma (ATA). A total of 63 patients with AERD and 79 patients with ATA were enrolled in this study. Analysis of mRNA expression of serine palmitoyl transferase, long-chain base subunit 2 (SPTLC2) and genotyping of ORMDL3 SNP (rs7216389) was performed. Significantly higher levels of SPTLC2 mRNA expression were noted in patients with AERD, which showed significant positive correlations with peripheral/sputum eosinophil counts and urine LTE4 (all P<0.05). The levels of SPTLC2 mRNA expression showed significant negative correlations with the level of FEV1 and FEV1/FVC (P = 0.033, r = -0.274; P = 0.019, r = -0.299, respectively). Genotype frequencies of ORMDL3 SNP (rs7216389) showed no significant differences between the AERD and ATA groups. Patients with AERD carrying the TT genotype of ORMDL3 had significantly lower levels of FVC (%) and PC20 methacholine than those carrying the CT or CC genotype (P = 0.026 and P = 0.030). This is the first study that shows the dysregulated de novo synthetic pathway of sphingolipids may be involved in the eosinophilic inflammation and airflow limitation in AERD.

Aspirin-exacerbated respiratory disease (AERD) is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC) for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA), and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (210-1) were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p = 3.40×10-8) in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954) showed the best AUC of 0.75 (asymptotic p-value of 7.94×10-21), with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be \"probably damaging\" to the structure and function of the protein, with a high score of '1'. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.

NSAIDs are the most frequent cause of hypersensitivity drug reactions. We have examined the association between NSAID-exacerbated respiratory disease (NERD) and genetic variants in arachidonic acid metabolism genes. We included 250 NERD patients, 260 NSAID-tolerant asthmatic (NTA) subjects and 315 healthy controls. Significant associations with NERD were identified for: rs3892408 C/C homozygous genotype (NERD vs NTA; p = 0.0001, pc = 0.0011; NERD vs controls; p = 0.0001, pc = 0.0011), rs5789 A/A homozygous genotype (NERD vs NTA; p = 0.0001, pc = 0.0011; NERD vs controls; p = 0.0001, pc = 0.0011), rs10306135 A/A homozygous genotype (NERD vs NTA; p = 0.0009, pc = 0.0091; NERD vs controls; p = 0.0064, pc = 0.045). Differences in copy number variations were also found (NERD vs NTA; p = 0.010; NERD vs controls; p = 0.0001). These results improve our understanding of the underlying mechanisms of NERD and may help develop a predictive test for this pathology. Original submitted 3 November 2014; Revision submitted 2 April 2015

Two common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin-exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population. A comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n = 264), NC (n = 238) and disease-control (aspirin tolerant asthma; ATA, n = 387) groups. The minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (P = 0.001, P = 0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (P = 0.039, 0.037, and 0.004, respectively). This implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype.

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 (210–1), 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.