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Background: Clinical features of aspirin-exacerbated respiratory disease (AERD) are characterized by overproduction of cysteinyl leukotrienes (LT) and eosinophil activation, in which epithelial cells contribute to eosinophilic airway inflammation. Folliculin (FLCN) helps maintain the integrity of epithelial barrier, but little is known about FLCN in AERD., Objective: We investigated the role of FLCN in the pathogenic mechanisms of AERD., Methods: We recruited 178 subjects with AERD, 276 subjects with aspirin-tolerant asthma (ATA) and 71 normal healthy controls (NC) at Ajou Medical Center. Levels of FLCN and interleukin (IL)-8 in sera and supernatants were measured by ELISA. Peripheral blood eosinophils isolated from asthmatic patients were cocultured with human airway epithelial cells (HAECs) pretreated with LTE 4 , dexamethasone and montelukast. The intracellular expressions of FLCN, tight (TJ) (occludins, claudin-1) and adherens (AJ) junctions (E-cadherin) were analysed by Western blotting. shRNA was used to down-regulate FLCN (shFLCN) in HAECs., Results: Serum FLCN levels were significantly higher in AERD group than in ATA and NC groups (all P < 0.001). The cut-off value of 56.6 pg/mL was used to define the high FLCN phenotype (highFLCN). Asthmatic patients with highFLCN were associated with increased airway hyperresponsiveness to methacholine (P = 0.015). The serum FLCN level could discriminate AERD group from NC group with 82% sensitivity (AUC = 0.793, P < 0.001). When HAECs were exposed to LTE 4 , FLCN release was increased significantly (P < 0.05), which were amplified along with disruption of TJ and AJ expressions when HAECs were cocultured with eosinophils and LTE 4 (all P < 0.05); these effects were suppressed by dexamethasone and montelukast. FLCN knockdown reduced IL-8 release and occludin expression from shFLCN HAECs., Conclusions: Our findings suggest that high LT and airway eosinophilia increased FLCN release from HAECs, which enhance epithelial activation and disruption. Modulation of FLCN may be a potential target for AERD., (© 2018 John Wiley & Sons Ltd.)

Introduction: Clinical features of aspirin-exacerbated respiratory disease (AERD) consist of moderate to severe asthma associated with chronic rhinosinusitis (CRS), which are derived from overproduction of cysteinyl leukotrienes along with chronic type 2 mediated inflammation in the upper and lower airway mucosa. Area covered: This review provides recent up-to-date information regarding phenotypes of AERD and encompasses comprehensive diagnostic methods and treatment options. To confirm the diagnosis of AERD, provocation testing via nasal, inhalation or the oral route of aspirin remains the gold standard; in vitro diagnostic methods are still not available. Essential management is to avoid cross-reacting cyclooxygenase 1 (COX-1) inhibitors along with use of highly selective COX-2 inhibitors and to maintain pharmacologic treatment depending on the severity of asthma and chronic rhinosinusitis. Recent biologics, including anti-IgE and anti-IL5 antibodies, are required in severe AERD patients with CRS. Aspirin desensitization can be recommended when indicated. Expert commentary: AERD is a heterogeneous disease in terms of severity and associated allergic disease. When performing diagnosis and treatment for AERD, such disease characteristics need to be kept in mind.

Purpose of Review: The pathophysiology of aspirin-exacerbated respiratory disease (AERD) is not fully understood and diagnostic methods and so far, treatments for AERD have not been standardized. We summarize recent research into the pathological mechanisms of AERD, diagnostic methods, and treatments for AERD patients., Recent Findings: In AERD pathophysiology, not only the reduced expression of E prostanoid 2 but also the dysfunction of its pathway could be involved. Moreover, eosinophils of AERD patients could be directly activated by aspirin to produce prostaglandin D2. Platelet activations are well known to be involved in AERD; however, plasma markers do not change during aspirin challenge tests. Additionally, novel genetic polymorphisms, such as P2RY12 and dipeptidyl peptidase 10 gene, and epigenetic predispositions of AERD were found. In AERD diagnosis, bronchial and nasal aspirin challenges have been applied in addition to oral challenge. Serum periostin has been suggested as a potential biomarker for AERD. Apart from standard pharmacological treatment and aspirin desensitization, biologics, including omalizumab and mepolizumab, as well as CRTH2 antagonists have been suggested as promising therapies for AERD treatment., Summary: AERD is usually associated with severe asthma phenotypes. AERD pathophysiology mainly involves the dysregulation of eicosanoid metabolisms, activations of effector cells, which could be influenced by genetic/epigenetic factors. Understanding the pathophysiology of AERD is key to improve the diagnostic methods and proper management of AERD patients.

Thyroid antibodies are frequently observed in urticaria patients, but their roles in urticaria are not clearly elucidated. We investigated the role of serum specific IgE to thyroid peroxidase (TPO) in patients with aspirin intolerant acute urticaria (AIAU) and aspirin intolerant chronic urticaria (AICU). We recruited 59 AIAU and 96 AICU patients with 69 normal controls (NC). Serum specific IgE to TPO was measured by manual direct ELISA, and CD203c expressions on basophil with additions of TPO were measured to prove a direct role of TPO in effector cells. The prevalences of serum specific IgE to TPO were significantly higher in AIAU (15.2%) and AICU groups (7.5%) compared to NC (0%, P=0.018: P=0.013, respectively). Flow cytometry showed CD203c induction in a dose dependent manner with serial additions of TPO in some AIAU and AICU patients having high specific IgE to TPO. Our findings show that the prevalence of serum specific IgE to TPO was significantly higher in both AIAU and AICU patients than in NC. It is suggested that specific IgE to TPO play a pathogenic role in AIAU and AICU.

Background: Aspirin-exacerbated respiratory disease (AERD) is an endotype of severe and eosinophilic adult asthma characterized by chronic rhinosinusitis with nasal polyps and hypersensitivity to aspirin and/or nonsteroidal anti-inflammatory drugs. A genetic contribution of dipeptidyl-peptidase 10 (DPP10) to asthma susceptibility and lung function decline has been reported. However, little is known about the role of DPP10 in the pathogenesis of AERD., Objective: To identify genetic variants of DPP10 that confer susceptibility to AERD or severe asthma., Methods: A case-control association study of DPP10 gene polymorphisms was performed in 3 groups of patients: 274 with AERD, 272 with aspirin-tolerant asthma, and 99 normal healthy controls. The rs17048175 single-nucleotide polymorphism was targeted based on a preliminary genomewide association study using an Affymetrix genomewide human single-nucleotide polymorphism array in a Korean population. DPP10, 15-hydroxyeicosatetraenoic acid, and YKL-40/chitinase-3-like protein were measured by enzyme-linked immunosorbent assay in sera taken from the study subjects., Results: There was a significant association between rs17048175 and the AERD phenotype, but not with aspirin-tolerant asthma. The DPP10 level was significantly higher in sera from patients with AERD compared with patients with aspirin-tolerant asthma and control subjects (P = .021 and P < .001, respectively). In addition, there was a significant difference of serum DPP10 level according to the single-nucleotide polymorphism (P = .001). Serum DPP10 level showed a strong correlation with 15-hydroxyeicosatetraenoic acid (r = 0.226, P = .017) and YKL-40 (r = 0.364, P = .004)., Conclusion: This study suggests a genetic contribution of rs17048175 to DPP10 in eosinophilic inflammation induction in the airways and to AERD susceptibility., (Copyright © 2015 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Aim: This study aimed to identify prognostic factors of aspirin-exacerbated respiratory disease by comparing clinical and genetic data with the clinical course., Patients & Methods: Patients were classified into two groups according to their response to inhalation rechallenge with lysine-aspirin after at least 1 year of regular treatment with antiasthmatic medications., Results: Forty eight patients (39.3%, group I) had negative responses, whereas 74 patients (60.7%, group II) had positive responses (n = 23) or were not rechallenged owing to persistent symptoms (n = 51). FEV₁ at diagnosis and follow-up were significantly lower in group II than in group I. The CCR3 polymorphism at -520T/G differed significantly between the two groups, whereas no difference was found in other SNPs., Conclusion: Baseline FEV₁ and lower lung function after treatment were clinical factors indicating a poor prognosis of aspirin-exacerbated respiratory disease. The G allele of CCR3 -520T>G was associated with persistent bronchial hypersensitivity to aspirin.

Various hypersensitivity reactions have been reported with aspirin and nonsteroidal anti-inflammatory drugs. Hypersensitivity can occur regardless of a chemical drug structure or its therapeutic potency. Allergic conditions include aspirin-exacerbated respiratory disease (AERD or aspirin-induced asthma), aspirin-induced urticaria/angioedema (AIU), and anaphylaxis. Several genetic studies on aspirin hypersensitivity have been performed to discover the genetic predisposition to aspirin hypersensitivity and to gain insight into the phenotypic diversity. This article updates data on the genetic mechanisms that govern AERD and AIU and summarizes recent findings on the molecular genetic mechanism of aspirin hypersensitivity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Persistent eosinophil activation in both the upper and lower airway mucosa is a central feature of aspirin-exacerbated respiratory disease (AERD). Eosinophil activation and survival are profoundly influenced by interleukin 5 (IL-5) and its receptor, IL-5R. In patients susceptible to allergic disorders, IL-5 receptor α (IL5RA) polymorphisms have been reported; however, an association with AERD remains unclear. We hypothesize that IL5RA polymorphisms may contribute to eosinophil activation in AERD patients. We recruited 139 AERD patients, 171 aspirin-tolerant asthma patients and 160 normal controls. IL5RA polymorphisms (-5993G>A, -5567C>G and -5091G>A) were genotyped and functional activity of polymorphism was assessed by luciferase reporter assay and electrophoretic mobility shift assay (EMSA). There was no significant difference in the genotype frequency of the three polymorphisms among the three groups. AERD patients carrying the AA genotype at -5993G>A had a significantly higher presence of serum-specific immunoglobulin E (IgE) to staphylococcal enterotoxin A (P=0.008) than those with the GG/GA genotype. In vitro, the -5993A allele had a higher promoter activity compared with the -5993G allele in human mast cell (HMC-1; P=0.030) and human promyelocytic leukemia (HL-60; P=0.013) cells. In EMSA, a -5993A probe produced a specific shifted band than the -5993G had. These findings suggest that a functional polymorphism in IL5RA may contribute to eosinophil and mast cell activation along with specific IgE responses to staphylococcal enterotoxin A in AERD patients.

Prostaglandin E2 receptor subtype EP4 (PTGER4) is one of the four subtypes of receptors for prostaglandin E2 (PGE2). Overproduction of cysteinyl leukotriene in mast cells may be related with suppression of PGE2 in patients with aspirin hypersensitivity. Considering the association of PTGER4 in mast cells, urticaria- and aspirin-related disease, we hypothesized the genetic variability of PTGER4 may be associated with aspirin-intolerant chronic urticaria (AICU). The case-control study was performed in 141 with AICU, 153 with aspirin-tolerant chronic urticaria (ATCU) and 174 with normal controls (NCs). PTGER4 promoter single-nucleotide polymorphism was genotyped using a primer extension method with the SNAPshot ddNTP primer extension kit. The functional variability of PTGER4 promoter polymorphism was carried out by dual-luciferase system and electrophoretic mobility shift assay (EMSA) in human mast cells (HMC-1). Furthermore, the effect of aspirin was performed for PTGER4 mRNA expression using real-time PCR, and PGE2 production was checked in HMC-1 cells using ELISA. AICU patients carrying GG genotype at -1254 G>A showed significantly higher frequency compared with NC (P=0.032). Similarly, the minor allele frequency, G allele was significantly higher in AICU compared with NC (P=0.031). In vitro functional study demonstrated that the -1254 G allele had lower luciferase activity (P<0.001) in HMC-1 cells. EMSA finding showed that PTGER4 -1254 G produced a specific band. Significantly decreased PTGER4 expression (P=0.008) and PGE2 production by aspirin exposure was confirmed in in vitro HMC cell line model (P=0.001). The PTGER4 -1254 G allele demonstrated a higher frequency in AICU patients and lower promoter activity with decreased expression of PTGER4 and contributes to the development of AICU.

Background: Aspirin-exacerbated respiratory disease (AERD) is a clinical syndrome associated with chronic inflammation in the airways coincident with chronic rhinitis, sinusitis, recurrent polyposis and asthma. Eosinophils are the key inflammatory cells in the development of AERD. AERD has been attributed to abnormalities of the arachidonic acid metabolism, but the pathogenesis of AERD is not fully understood. Our aim was to investigate the genetic contribution of the arachidonate 15-lipoxygenase gene (ALOX15) to the development of AERD., Methods: We enrolled 171 patients with AERD, 229 patients with aspirin-tolerant asthma, and 195 normal healthy controls in a Korean population. Three polymorphisms (-427G/A, -272C/A, -217G/C) in the promoter region of ALOX15 were genotyped. The functional variability of the promoter polymorphisms were analyzed by luciferase reporter activity assay., Result: No significant difference in the genotype frequency of the ALOX15 genetic polymorphism was found. Peripheral total eosinophil count was significantly higher in the patients carrying the GG genotype of the -427G/A polymorphism (p = 0.016). Similarly, the patients carrying haplotype 1 (ht1) (GCG) of -427G/A, -272C/A and -217G/C showed a significantly higher total eosinophil count compared to the other haplotypes (p = 0.008) in the AERD group. The promoter activity of the ht1 (GCG) construct was significantly higher compared to that of the ht3 (AGG) construct in A549 and U937 cells (both p < 0.001)., Conclusion: These results suggest that the promoter polymorphisms of the ALOX15 gene affect ALOX15 activity leading to increased eosinophil infiltration in AERD patients., (Copyright © 2012 S. Karger AG, Basel.)

Objective: Aspirin affects interleukin-4 (IL-4) synthesis; however, the genetic role of IL-4 has not been evaluated in asthmatics with aspirin hypersensitivity. The objective of the study was to examine the influence of single nucleotide polymorphisms (SNPs) in IL-4 gene on aspirin hypersensitivity in asthmatics at the genetic and molecular levels., Methods: Aspirin-intolerant (AIA, n=103) and aspirin-tolerant asthmatics (n=270) were genotyped and functional promoter assays were performed., Results: Of 15 SNPs tested, seven (-589T>C (rs2243250) in promoter, -33T>C (rs2070874) in the 5'-untranslated region, +4047A>G (rs2243266), +4144C>G (rs2243267), +4221C>A (rs2243268), +4367G>A (rs2243270), and +5090A>G (rs2243274) in introns) were significantly associated with AIA risk. The frequency of the rare allele (C) of -589T>C was higher in the AIA group than in the aspirin-tolerant asthmatic group (P=0.016), and a gene dose-dependent decline in forced expiratory volume in 1 s was noted after an aspirin challenge (P=0.0009). Aspirin unregulated IL-4 mRNA production in Jurkat T and K562 leukemia cells. A reporter plasmid assay revealed that aspirin augmented IL-4 promoter transactivation with the -589T>C C and -33T>C C alleles, compared with that bearing the -589T>C T and -33T>C T alleles. Further, electrophoretic mobility shift assay showed the formation of nuclear complexes with -33T>C and -589T>C allele-containing probes; this was augmented by aspirin. The complexes formed with the -33T>C and -589T>C probes were shifted by treatment with anti-CCAAT-enhancer-binding proteins β and anti-nuclear factor of activated T-cells antibodies, respectively, indicating the inclusion of these transcription factors., Conclusion: Aspirin may regulate IL4 expression in an allele-specific manner by altering the availability of transcription factors to the key regulatory elements in the IL4 promoter, leading to aspirin hypersensitivity.

Aims: Cysteinyl leukotrienes are inactivated by acetyl coenzyme A-dependent N-acetyltransferase (NAT). Thus, functional alterations of the NAT gene may contribute to the risk of aspirin-intolerant asthma., Materials & Methods: Asthmatics (n = 438) were categorized into aspirin-intolerant asthma (15% or greater decrease in the forced expiratory volume in 1 s or cutaneous reactions, n = 170) or aspirin-tolerant asthma (n = 268) groups. In total, 14 polymorphisms of the NAT2 gene were genotyped by a single-base extension method., Results: The distributions of all loci of the 14 SNPs were in Hardy-Weinberg equilibrium (p > 0.05). Among the 14 SNPs, six common SNPs (minor allele frequency >5%) in a Korean population were used for haplotype construction and further statistical analysis. The logistic regression analysis demonstrated that NAT2 -9246G>C and haplotype 2 (TCACGG) were significantly associated with the risk of aspirin-intolerant asthma. The rare allele frequencies of the SNP and Ht2 were significantly higher in the aspirin-intolerant asthma group than in the aspirin-tolerant asthma group (p(corr) = 0.03 and p(corr) = 0.02 in codominant model)., Conclusion: In a large genetic epidemiology study of aspirin-intolerant asthma in a Korean population, genetic polymorphisms of NAT2 were found to be related to a risk of aspirin hypersensitivity among asthmatics.

Introduction: Aspirin hypersensitivity represents two distinct clinical syndromes, such as aspirin exacerbated respiratory disease (AERD) and aspirin-intolerant chronic urticaria/angioedema (AICU) which have different clinical phenotypes resulting from different genetic backgrounds in a Korean population. Persistent eosinophilic inflammation in airway is a characteristic feature of AERD and chemokine CC motif receptor 3 (CCR3) plays an important role in eosinophilic infiltration into the asthmatic airway., Objectives: The main objective of this study is to investigate the association between CCR3 gene polymorphisms and aspirin hypersensitivity, including AERD and AICU., Methods: CCR3 mRNA expression was measured after an aspirin provocation test by real-time PCR. In total, 330 patients with aspirin hypersensitivity (191 AERD and 139 AICU) and 217 normal healthy controls (NC) were genotyped for two CCR3 promoter polymorphisms (-520T/G and -174C/T), and the functional effects of the polymorphisms were analyzed applying a luciferase reporter assay and an electrophoretic mobility shift assay., Results: CCR3 mRNA expression was significantly increased after aspirin provocation in AERD patients (P=0.002) but not in AICU patients. An in vitro functional study showed that the reporter construct having a -520G allele exhibited significantly higher promoter activity compared with the construct having a -520T allele in human myeloid (U937), lymphoid (Jurkat), and mast (HMC-1) cell lines (P<0.001). We found -520G and -174T specific bands on EMSA., Conclusion: This result suggests that the CCR3 genetic polymorphisms may contribute to the development of the AERD phenotype and may be used as a genetic marker for differentiating between the two major aspirin hypersensitivity phenotypes.

In asthmatic airways, adenosine is a potent bronchoconstrictor with either pro- or anti-inflammatory effects depending on receptor interactions. While aspirin has been suggested to mediate adenosine action, the roles of adenosine and its receptors in aspirin-intolerant asthma (AIA) are not well-defined. Therefore, we evaluated associations between genetic polymorphisms of adenosine deaminase and the four adenosine receptors (A(1), A(2A), A(2B), and A(3)) with the AIA phenotype. The genes for adenosine deaminase (ADA) and the four adenosine receptors (ADORA1, ADORA2A, ADORA2B, and ADORA3) were screened by direct sequencing, and 13 single nucleotide polymorphisms (SNPs) were selected among 23 polymorphisms. Using multivariate logistic regression analysis, we compared the frequencies of SNP genotypes and haplotypes among 136 patients with AIA, 181 patients with aspirin-tolerant asthma (ATA), and 183 normal individuals. We found significant differences between normal and patients with AIA in the ADORA1 SNP genotype frequencies for 1405C>T (P=0.001) and A102A (P=0.013). No other significant associations were detected for the other SNPs. In the haplotype analysis, ht[C-T-G] (P=0.003) and ht[A-C-G] (P=0.032) in ADORA1 and ht[A-T] in ADORA2 (P=0.013) were significantly associated with AIA. Genetic polymorphisms of adenosine receptors A(1) and A(2A) were associated with AIA, suggesting that adenosine might play a crucial role in the development of AIA through interactions with the A(1) and A(2A) receptors.

Background and Objective: Obesity is an important factor in the development of asthma. Aspirin hypersensitivity affects 5-10% of asthmatics. The association between obesity and aspirin hypersensitivity in asthma is unclear. This study evaluated the association of BMI and asthma in patients with aspirin-tolerant asthma (ATA) and aspirin-intolerant asthma (AIA)., Methods: Aspirin provocation tests were performed in 667 asthmatic patients and changes in FEV(1) were used to categorize patients as ATA or AIA. The BMI of asthmatics was graded using the percentile BMI of 406 normal controls., Results: Aspirin-induced changes in FEV(1)% ranged from 15% to 68%. Compared with the controls, the ATA group had a higher BMI (24.5 +/- 0.1 vs 23.8 +/- 0.2 kg/m(2), P = 0.001). The AIA group had a lower BMI. The aspirin-induced percentage fall in FEV(1) was inversely correlated with BMI in asthmatic patients (r = -0.094, P = 0.016). BMI was correlated with age and PC20, but not with FEV(1) in asthmatic patients. In a logistic regression adjusted for age, gender, and smoking status, FEV(1) and PC20 were associated with AIA with odds ratios of 0.986 and 0.586, respectively. BMI was associated with AIA with an odds ratio of 0.916., Conclusions: Aspirin intolerance in asthmatics explains the lesser association with obesity. Obesity is not a risk factor in the development of asthma in patients with AIA.

Background and Objective: The high-affinity IgE receptor comprises a tetramer of the ligand-binding alpha chain, a signal-augmenting beta chain, and a signal-transducing gamma chain dimer on mast cells. We hypothesized that the three subsets of the FCER1 gene may play a role in the development of the aspirin-intolerant asthma (AIA) phenotype and analyzed these genetic polymorphisms in association with clinical parameters in AIA patients., Subjects and Methods: Six polymorphisms of FCER1 (FCERIA-344C>T, FCER1A-95T>C, MS4A2-109T>C, MS4A2 E237G, FCER1G-237A>G, FCER1G-54G>T) were genotyped in 126 AIA patients compared to 177 patients with aspirin-tolerant asthma (ATA) and 222 normal health controls (NC)., Results: A significant difference in the genotype frequencies of FCER1G-237A>G was detected between AIA and ATA patients (p<0.05) both in co-dominant and recessive analysis models, whereas no significant relationships were identified between the frequencies of the other five single-nucleotide polymorphisms and AIA, ATA, and NC subjects. In addition, AIA patients carrying the homozygous AA genotype of FCER1G-237A>G exhibited significantly higher total serum IgE levels than did those with the GG/AG genotype (p=0.012). AIA patients expressing the CT/TT genotype at FCERIA-344C>T showed a higher prevalence of serum IgE specific to Staphylococcal enterotoxin A than did those with the CC genotype (p=0.008)., Conclusion: The FCER1G-237A>G and FCERIA-344C>T polymorphisms may contribute to the development of AIA in a Korean population.

Introduction: Aspirin-intolerant asthma (AIA), a major clinical presentation of aspirin hypersensitivity, affects 10% of adult asthmatics. The genetic risk factors involved in the susceptibility to AIA have recently been investigated, but multilocus single-nucleotide polymorphisms (SNPs) associated with this susceptibility has not been evaluated., Methods: We examined 246 asthmatic patients: 94 having aspirin intolerance and 152 having aspirin tolerance. We selected 23 SNPs of 13 candidate genes and genotyped each SNP using a primer extension method. Multilocus genetic interactions were examined using multifactor dimensionality reduction (MDR) to test all multilocus SNP combinations to identify a useful SNP set for predicting the AIA phenotype., Results: We identified the best model using the MDR method, which consisted of a four-locus gene-gene interaction with 65.16% balanced accuracy and a cross-validation consistency of 70% in predicting AIA disease risk among asthmatic patients. This model included four SNPs such as B2ADR 46A>G, CCR3-520T>G, CysLTR1-634C>T, and FCER1B-109T>C., Discussion: These results suggest that a multilocus SNP acts in combination to influence the susceptibility to aspirin intolerance in asthmatics and could be a useful genetic marker for the diagnosis of AIA.

Chronic urticaria (CU) associated with aspirin sensitivity, termed aspirin-intolerant CU (AICU), is a common condition in the general population. The genetic mechanism of AICU still is not fully understood. We investigated genetic polymorphisms of FcepsilonR1beta and FcepsilonR1gamma in patients with CU including AICU and aspirin-tolerant CU (ATCU) by analyzing the genotypes and haplotypes of four subsets of FcepsilonR1 genes in association with various clinical parameters. Four polymorphisms of FcepsilonR1 (FcepsilonR1beta -109T>C, FcepsilonR1beta E237G, FcepsilonR1gamma -237A>G, and FcepsilonR1gamma -54G>T) were genotyped in 119 AICU patients and compared with 154 patients with ATCU and 224 normal healthy controls (NCs). No significant differences were observed with respect to the allele and genotype frequencies of all four FcepsilonR1 single-nucleotide polymorphisms (SNPs; p > 0.05) in CU including AICU and ATCU patients. However, two SNPs at FcepsilonR1beta E237G and FcepsilonR1gamma -237A>G were associated with atopy in AICU patients but not in ATCU. AICU patients with the AG/GG genotype of FcepsilonR1beta E237G and FcepsilonR1gamma -237G allele had a significantly higher frequency of atopy than those with the AA genotype (p = 0.02 and p = 0.040), respectively. The release of histamine from basophils induced by anti-IgE antibodies was significantly higher in AICU patients than in NCs and was increased in atopic patients compared with nonatopic patients (p = 0.006 and p = 0.007, respectively). The FcepsilonR1beta E237G and FcepsilonR1gamma -237T>G polymorphisms may be associated with the rate of atopy, which in turn could increase the release of histamine from basophils and may lead to the development of the AICU phenotype.

The pathogenic mechanism of acetyl salicylic acid (ASA)-induced urticaria (AIU) is not fully understood. We compared the levels of neutrophil activation and related cytokines in patients with ASA-intolerant acute urticaria (AIAU) and ASA-intolerant chronic urticaria (AICU). A total of 51 patients with AIAU, 88 patients with AICU, and 102 normal controls (NC) were enrolled in this study. The serum levels of myeloperoxidase (MPO), interleukin-8 (IL-8), and IL-18 were compared among the three groups. The serum levels of MPO were highest in the AIAU group, followed by the AICU and NC groups, and the serum levels of IL-18 were significantly higher in the AIAU and AICU groups than in NC group. Within the AIU groups, significant correlations were noted between the levels of MPO and IL-8, and IL-8 and IL-18. In conclusion, neutrophil activation, which was associated with the levels of IL-8 and IL-18 in the AIAU group, may be involved in the pathogenic mechanism of AIU. A role for IL-18 in the pathogenesis of AIU is also suggested.

Leukotriene overproduction is the major characteristic of aspirin-intolerant asthma (AIA). Most studies examining the molecular genetic mechanisms of AIA have focused on leukotriene-related genes, including ALOX5, LTC4S, TXA2R and prostanoid-receptor genes. One study suggested that the human leukocyte antigen (HLA) allele DPB1*0301 may be a genetic marker for the AIA phenotype in European and Asian populations, and HLA-DPB1*0301 has been suggested as a useful genetic marker for predicting more favorable responders to leukotriene-receptor antagonists for long-term management of AIA. Although several reports have indicated possible associations between genetic polymorphisms and variable responses to leukotriene modifiers in nonaspirin sensitive asthmatic patients, few have suggested relationships between such genetic polymorphisms and variable responses to asthma drugs in AIA patients.

The genetic mechanism of aspirin intolerant acute urticaria (AIAU) is unknown. To demonstrate an association between the beta 2 adrenergic receptor (ADRB2) polymorphism and the phenotype of AIAU, one hundred fourteen patients with AIAU, 110 patients with aspirin intolerant chronic urticaria (AICU), and 498 normal healthy controls (NC) based on a Korean population were enrolled. The genotype of ADRB2 at 46 A > G was analyzed using a direct sequencing method. The ADRB2 polymorphism at 46 A > G showed a significant difference between AIAU and NC; the frequency of the major genotype was significantly higher in the AIAU group (p= 0.017 in recessive model), while no differences were noted in allele and genotype frequencies between AICU and NC. In conclusion, the ADRB2 (46 A > G) gene polymorphism may contribute to the development of the phenotype of AIAU.

In this study, we compared the roles of CysLT receptor type 1 (CysLTR1) and leukotriene C4 synthase (LTC4S) gene polymorphisms in two major aspirin-related allergic diseases, aspirin-intolerant asthma (AIA) and aspirin-induced chronic urticaria/angioedema (AICU). CysLTR1-634C>T and LTC4S-444A>C polymorphisms were genotyped and its functional effect on the promoter activity was compared. As in vivo functional study, changes of peripheral mRNA level of CysLTR1 were measured by real-time PCR before and after aspirin challenge. A significant association was found for the CysLTR1 promoter polymorphism and the AIA phenotype compared to AICU (P = 0.015). In U937 cells, the variant genotype reporter construct showed significantly higher promoter activity than the common genotype (P < 0.05). The CysLTR1 mRNA levels increased significantly after aspirin challenge in AIA patients (P = 0.013). In conclusion, the CysLTR1 polymorphism may contribute to develop to the AIA phenotype and be used as a genetic marker for differentiating two major aspirin hypersensitivity phenotypes.

Objectives: Leukotriene receptor antagonists (LTRA), such as montelukast, have been used as a first-line treatment for patients with aspirin-intolerant asthma (AIA). This study evaluated associations between the clinical requirement for LTRA and genetic polymorphisms of the ALOX5, LTC4S, COX-2, CysLTR1 and TBXA2R genes in the arachidonic acid cascade in the long-term management of 89 AIA patients from a Korean population., Methods: Asthma control status was monitored for 1 year with maintenance medications of inhaled corticosteroid and oral LTRA, and AIA patients were classified into three groups according to the mean montelukast dose required per month to maintain asthma control for 1 year: group I (> or = 200 mg montelukast/month; n = 37), group II (5-150 mg/month; n = 25) and group III (< 5 mg/month; n = 27). Genetic polymorphisms in the arachidonic acid cascade were determined using a single-base extension method., Results: We found that there was a significant difference in the genotype frequency of the CysLTR1 promoter polymorphism -634C > T among the three groups (p = 0.007 for group I vs group II, p = 0.017 for group I vs group III), while there were no significant associations between LTRA requirements and polymorphisms of the other genes. The patients with the variant genotype (CT or TT) of the -634C = T CysLTR1 promoter polymorphism showed a higher expression level than those with the common genotype (CC)., Conclusion: These findings indicate that the CysLTR1 promoter polymorphism is a useful genetic marker for predicting LTRA requirements in the long-term management of AIA patients.

Background: Genetic predisposition is linked to the pathogenesis of aspirin-intolerant asthma. Most candidate gene approaches have focused on leukotriene-related pathways, whereas there have been relatively few studies evaluating the effects of polymorphisms in prostanoid receptor genes on the development of aspirin-intolerant asthma. Therefore, we investigated the potential association between prostanoid receptor gene polymorphisms and the aspirin-intolerant asthma phenotype., Methods: We screened for genetic variations in the prostanoid receptor genes PTGER1, PTGER2, PTGER3, PTGER4, PTGDR, PTGIR, PTGFR, and TBXA2R using direct sequencing, and selected 32 tagging single nucleotide polymorphisms among the 77 polymorphisms with frequencies >0.02 based on linkage disequilibrium for genotyping. We compared the genotype distributions and allele frequencies of three participant groups (108 patients with aspirin-intolerant asthma, 93 patients with aspirin-tolerant asthma, and 140 normal controls)., Results: Through association analyses studies of the 32 single nucleotide polymorphisms, the following single nucleotide polymorphisms were found to have significant associations with the aspirin-intolerant asthma phenotype: -616C>G (P=0.038) and -166G>A (P=0.023) in PTGER2; -1709T>A (P=0.043) in PTGER3; -1254A>G (P=0.018) in PTGER4; 1915T>C (P=0.015) in PTGIR; and -4684C>T (P=0.027), and 795T>C (P=0.032) in TBXA2R. In the haplotype analysis of each gene, the frequency of PTGIR ht3[G-G-C-C], which includes 1915T>C, differed significantly between the aspirin-intolerant asthma patients and aspirin-tolerant asthma patients (P=0.015)., Conclusion: These findings suggest that genetic polymorphisms in PTGER2, PTGER3, PTGER4, PTGIR, and TBXA2R play important roles in the pathogenesis of aspirin-intolerant asthma.

Background: Although the mechanism that underlies aspirin hypersensitivity is not completely understood, an IgE-mediated response was reported for a patient with aspirin-intolerant chronic urticaria (AICU)., Objective: We investigated whether genetic polymorphisms on the alpha-chain of the high-affinity IgE receptor (FcepsilonRIalpha) gene were associated with the AICU phenotype., Methods: We genotyped 2 promoter polymorphisms (-344C>T and -95T>C) of FcepsilonRIalpha gene in the Korean population, and the functional effect of the -344C>T polymorphism was analyzed by using a luciferase reporter assay and an electrophoretic mobility shift assay., Results: The rare allele frequency of the -344C>T polymorphism was significantly higher in the patients with AICU compared with the other subjects (P= .008 for AICU vs aspirin-tolerant chronic urticaria; P= .03 for AICU vs controls). This polymorphism was also significantly associated with total serum IgE concentrations and a higher rate of atopy in the patients with AICU (P= .01 and .05, respectively). The reporter plasmid that carried the -344T allele exhibited significantly higher promoter activity in a rat mast cell line (RBL-2H3) compared with the promoter activity of the -344C allele (P< .001). We found that transcription factor Myc-associated zinc finger protein preferentially bound the -344C promoter. Moreover, patients with AICU with the heterozygous CT genotype of the -344C>T polymorphism exhibited greater anti-IgE-mediated histamine release compared with those with the homozygous CC genotype., Conclusion: These results suggest that the -344C>T polymorphism of the FcepsilonRIalpha promoter may be associated with increased expression of FcepsilonRIalpha on mast cells and enhanced release of histamine., Clinical Implications: The FcepsilonRIalpha -344C>T polymorphism may contribute to the development of AICU.

Purpose of Review: Aspirin-induced urticaria/angioedema is a major aspirin-related hypersensitivity often associated with aspirin-intolerant asthma. Genetic studies on aspirin-intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes. The genetic analysis of aspirin-induced urticaria/angioedema is limited, however., Recent Findings: A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin-induced urticaria/angioedema. A polymorphism study that examined nine single-nucleotide polymorphisms of five leukotriene-related genes [ALOX5 (encoding 5-lipoxygenase), ALOX5AP (5-lipoxygenase-activating protein), PTGS2 (cyclooxygenase 2), LTC4S (leukotriene C4 synthase), and CYSLTR1 (cysteinyl leukotriene receptor 1)] found that promoter polymorphisms of ALOX5 (-1708A>G) and CYSLTR1 (-634C>T) were significantly different between aspirin-intolerant asthma and aspirin-induced urticaria/angioedema, suggesting different contributions to the lipoxygenase pathway. A second polymorphism study, conducted on histamine-related genes, did not find any significant associations with aspirin-induced urticaria/angioedema for the genes HNMT (encoding histamine N-methyltransferase), HRH1 or HRH2 (encoding histamine receptor types 1 and 2 respectively), or the gene encoding high-affinity IgE receptor Ibeta (FcepsilonRIbeta); however, the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin-induced urticaria/angioedema. This finding has been supported by in vitro functional studies., Summary: The HLA alleles DRB11302 and DQB10609, and the ALOX5 and FcepsilonRIalpha promoter polymorphisms, may contribute to the pathogenesis of aspirin-induced urticaria/angioedema. Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition.

Several studies have suggested the involvement of an autoimmune mechanism in aspirin (ASA)-intolerant asthma. To test this hypothesis, we measured the levels of circulating autoantibodies, such as IgG and IgA to tissue transglutaminase (TGase), IgG to cytokeratins (CKs) 8, 18, and 19, Clq-binding immune complex (CIC), and antinuclear antibody (ANA), in the sera of 79 patients with ASA-intolerant asthma (Group I) and those of two control groups, consisting of 61 patients with ASA-tolerant asthma (Group II) and 88 healthy control subjects (Group III) by means of ELISA. Significantly higher prevalences of IgG antibodies to CK18 (13.9%) and CK19 (17.7%) were noted in Group I, as compared with Group III (p<0.05 for all) not with Group II. Regarding the prevalences of other autoantibodies, the levels of ANA (1.3%), IgG to TGase (3.8%), and CIC (24.7%) in Group I were not significantly different from those in Groups II and III. Significant correlations were found between positivities for the anti-CK18 and anti-CK19 autoantibodies and the PC(20) methacholine values in the analysis of asthma Groups I and II vs. normal controls, (p=0.001 and p=0.003, respectively). Further studies are needed to explore the potential involvement of an autoantibody-mediated mechanism in the clinical manifestation of bronchial asthma.

Aspirin-induced asthma (AIA) and aspirin-induced urticaria/ angioedema (AIU) are two major aspirin-related allergies. We summarize recent findings related to their molecular genetic mechanisms in order to identify genetic susceptibility markers for differentiating AIU and AIA. The overproduction of cysteinyl leukotriene has been suggested as a mechanism in both AIU and AIA. Increased expression of CYSLTR1 with CYLSTR1 and CYSLTR2 polymorphisms are new findings in AIA, while the ALOX5 promoter polymorphism has been noted in AIU. An HLA study suggested that DPB1*0301 is a strong genetic marker for AIA, and that HLA DRB1*1302 and DQB1*0609 are markers for AIU susceptibility. Several single nucleotide polymorphisms (SNPs) in the promoters of EP2, TBX21, COX-2, Fc epsilon RIbeta, and TBXA2R were associated with AIA, while an Fc epsilon RIalpha promoter polymorphism was associated with AIU. The functional studies of the key genes involved in AIA and AIU are summarized. The identification and functional study of genetic markers for AIA and AIU susceptibility would further elucidate the pathogenic mechanisms and facilitate the development of early diagnostic markers to establish therapeutic targets.

Purpose of Review: To summarize recent findings related to the pathogenic mechanisms of aspirin-induced asthma with emphasis on molecular genetic mechanisms., Recent Findings: The overproduction of cysteinyl leukotrienes with the increased expression of cysteinyl leukotriene receptor 1 (CYSLTR1) is a consistent finding in aspirin-induced asthma patients. Recent data have suggested a dysregulation of cyclooxygenase-2 and prostaglandin E2, increased levels of 15-hydroxyeicosatetranoic acid, and decreased lipoxin generation as characteristics of the condition. The HLA allele DPB10301 was documented as a strong genetic marker for susceptibility in an Asian population. Leukotriene C4 synthase has been established as a key genetic determinant of aspirin-induced asthma, but recent studies have demonstrated that several single nucleotide polymorphisms in the promoters of prostaglandin E2 receptor subtype 2, CYSLTR1 and CYSLTR2 and T-box expressed in T cells (TBX21) could increase risk for the condition. Although cyclooxygenase-2 and thromboxane A2 receptor polymorphisms were not associated with aspirin-induced asthma phenotype, they may exert functional effects., Summary: The identification of genetic markers for aspirin-induced asthma susceptibility along with in-vitro functional studies would help to elucidate the pathogenesis of the condition. Further studies of the interactions among genes and between genes and the environment will be essential.

Aspirin-intolerant asthma (AIA) is a distinct clinical syndrome that refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). It is widely recognized that increased cysteinyl leukotriene (cysLT) biosynthesis is associated with the development and progression of AIA. Leukotriene C4 synthase (LTC4S) is the terminal enzyme in cysLT production and is a strong candidate gene in the pathogenesis of aspirin-intolerant asthma (AIA). In this paper, we report a new single nucleotide polymorphism (SNP) of the LTC4S promoter, -1702G>A, in AIA patients and evaluate its genetic role in the association with the LTC4S-444 A>C polymorphism. We enrolled 110 AIA patients, 125 aspirin-tolerant asthma (ATA) patients, and 125 normal controls. SNP genotyping of the LTC4S-1702G>A and -444A>C polymorphisms was performed using SNP-IT assays. Haplotype analyses were performed using Haploview version 2.05, which is based on an estimation-maximization (EM) algorithm. There were no significant differences in the allele or genotype frequencies of the LTC4S-1702G>A and -444A>C polymorphisms among the three groups (p > 0.05), with no significant differences in the observed haplotype frequencies (p > 0.05). Moreover, no significant associations were found between the genotype of each SNP in AIA patients with the clinical characteristics, including a forced expiratory volume in one second (FEV1) %, a provocation concentration of methacholine to induce more than 20% decrease of FEV1 (PC20) to methacholine, and serum total IgE levels (p > 0.05). These results indicate that there is no association between these two promoter polymorphisms of LTC4S and the phenotype of AIA in a Korean population.

The pathogenesis of aspirin (acetylsalicylic acid, ASA)-intolerant urticaria (AIU) is still poorly understood but it has recently been suggested that it is associated with the overproduction of leukotriene (LT). This is supported by evidence that cyclooxygenase 2 inhibitor is given safely to patients with AIU. The present study was designed to investigate the role of genetic polymorphism of LT related genes in the pathogenesis of AIU via a case-control study. We screened single nucleotide polymorphisms (SNPs) in genes encoding enzymes involved in leukotriene synthesis in the Korean population with AIU (n = 101), ASA-intolerant asthma (AIA, n = 95) and normal healthy controls (n = 123). Genotype was determined by primer extension reactions using the SNapShot ddNTP primer extension kit. Among 8 SNPs of four LT related genes, the polymorphism of ALOX5 at positions of -1708 G > A showed significant difference in genotype frequency between AIU and AIA (p = 0.01). Furthermore, there were significant differences observed in the frequencies of two ALOX5 haplotypes between the AIU group and AIA group (p < 0.05). However, there were no differences in allele, genotype, or haplotype frequencies of ALOX5 between the AIU group and the normal control group. These results suggested that ALOX5 has a differing contribution in two major clinical pathogenesis related to ASA-sensitivity.

Background: Glutathion S-transferase P1 (GSTP1), the abundant isoform of glutathione S-transferase in lung epithelium, plays an important role in cellular protection against oxidative stress and toxic foreign chemicals. GSTP1 (Ile105Val) polymorphism has been reported to be associated with asthma related phenotypes such as atopy and bronchial hyperresponsiveness. Therefore we investigated whether this polymorphism may be associated with the development of aspirin-intolerant asthma (AIA)., Methods: GSTP1 Ile105Val polymorphism was determined using a single based extension method in 88 AIA subjects and compared to 154 aspirin-tolerant asthma (ATA) subjects and 119 normal healthy controls (NC) recruited from the Korean population., Results: No significant differences in allele and genotype frequencies of the GSTP1 Ilel105Val polymorphism were observed in the three groups (p>0.05). However, minor G allele frequency of the GSTP1 Ilel105Val polymorphism in AIA group (16.5%) tended to be lower than in the NC group (20.6%)., Conclusion: These results suggest a lack of association of the GSTPI Ilel105Val gene polymorphism with AIA phenotype in the Korean population [word count: 159].

Objectives and Methods: The cysteinyl leukotriene receptor 2 (CYSLTR2) gene on chromosome 13q14.12-q21.1 encodes a receptor for CYSLTs, potent biological mediators in the pathogenesis of asthma, particularly that associated with aspirin intolerance (AIA). In an effort to discover additional polymorphism(s), the variant(s) of which have been implicated in asthma and aspirin intolerance, we scrutinized genetic polymorphisms of the CYSLTR2 gene, and evaluated this locus as a potential candidate for asthma., Results: DNA sequencing in 24 Koreans of the 5-kb region of the CYSLTR2 gene, including the approximately 1500-bp promoter region, revealed four sequence variants: one in the 5'-flanking region (c.-819T>G), two in the 3'-flanking region (c.2078C>T and c.2534A>G), and one downstream of the gene (c.2545+297A>G). The SNP frequencies were 0.499 (c.-819T>G), 0.351 (c.2078C>T), 0.429 (c.2534A>G), and 0.088 (c.2545+297A>G), and five haplotypes were constructed. The SNPs and haplotypes were not associated with risk of asthma development, but were significantly associated with aspirin intolerance. The frequencies of rare alleles on c.-819T>G, c.2078C>T, and c.2534A>G were higher in subjects with AIA than in subjects with aspirin-tolerant asthma (P=0.013-0.031). Asthmatics who had rare alleles for c.-819T>G, c.2078C>T or c.2534A>G exhibited a more pronounced fall in FEV1 after aspirin provocation than did those who carried the common allele (P=0.03-0.009). Asthmatics carrying ht2 (TTGA) also showed a more pronounced decrease in FEV1% after aspirin provocation than those carrying ht1 (GCGA) (P=0.006). These associations were even stronger when combined with LTC4S polymorphisms (-444A>C [c.-444A>C]) gene., Conclusion: CYSLTR2 polymorphisms are associated with aspirin intolerance in asthmatics.

Introduction: Aspirin is a popular nonsteroidal anti-inflammatory drug, but some patients suffer from hypersensitivity to it. This prompted us to identify the factors or molecules related to these responses., Material/methods: A commercially available DNA microarray was used to study changes in gene expression in human peripheral blood mononuclear cells (PBMCs) after aspirin treatment. The PBMCs were collected from a patient with aspirin-intolerant asthma and one normal healthy control., Results: We identified 61 and 107 genes respectively induced and repressed by aspirin treatment in the PBMCs derived from the normal control. In the patient showing aspirin-induced asthma responses, 31 genes were up-regulated and 6 were down-regulated after aspirin treatment. Among these,1 gene was expressed with the same pattern in the control and the patient. In contrast, 19 genes showed different expression patterns, and it turned out that most of them were involved in immune responses, cell growth/proliferation, transcription/translation, and signaling pathways., Conclusions: These results show the molecules involved in hypersensitivity to aspirin and may lead to a better understanding of adverse responses to aspirin. Furthermore, they can provide clues for identifying novel therapeutic and/or preventive molecular targets of the adverse effects of aspirin.

A recent study has demonstrated the possible involvement of a leukotriene C4 synthase (LTC4S) gene polymorphism in ASA-intolerant asthma (AIA) in a Polish population, whereas no significant association was noted in other populations. To investigate the role of genetic polymorphism in AIA development, we screened single nucleotide polymorphisms (SNPs) of the key enzymes involved in arachidonate metabolism, and the cysteinyl leukotriene receptor 1 (CYSLTR1) in a large Korean population with AIA: 93 AIA and 181 ASA-tolerant asthma (ATA) patients, and 123 normal controls. The single-base extension method was used to genotype SNPs in 5-lipoxygenase (ALOX5, -1708G-->A, 21C-->T, 270G-->A, 1728G-->A), ALOX5-activating protein (ALOX5AP, 218A-->G), prostaglandin-endoperoxide synthase 2 (PTGS2, COX2, -162C-->G, 10T-->G, R228H, V511A), LTC4S (-444A-->C), and CYSLTR1 (927T-->C). Haplotype analyses were undertaken for the SNPs in ALOX5. No significant differences in allele and genotype frequencies of single SNPs were observed between the patient groups ( P>0.05). However, the frequency of the ALOX5-ht1[G-C-G-A] haplotype in the AIA group was significantly higher than its frequency in the ATA group with a probability ( P) of 0.01, odds ratio (OR) of 5.0, and 95% confidence interval (95%CI) of 1.54-17.9, and in the normal controls ( P=0.03, OR=4.5, 95%CI=1.1-18.4), by using a dominant model. These results suggest a lack of association between the ALOX5AP, PTGS2, LTC4S, and CYSLTR1 gene polymorphisms and the AIA phenotype in the Korean population. However, the possible involvement of ALOX5-ht1[G-C-G-A] in AIA development is suggested.

To investigate the pathogenic mechanism of late asthmatic response in comparison to early asthmatic response, changes of serum neutrophil chemotactic activity (NCA) using the Boyden chamber method and histamine level using the automated fluorometric analyzer were observed in 13 aspirin (ASA)-sensitive asthma subjects (group I: 7 early responders and group II: 6 dual responders) during lysine aspirin bronchoprovocation test (L-ASA BPT). Sera were collected before, and 30 min and 240 min after L-ASA BPT. Serum NCA increased significantly after 30 min (p=0.02) and decreased significantly at 240 min (p=0.02) in group I, while serum NCA of group II increased significantly at 30 min (p=0.04), tending to increase further up to 240 min with no statistical significance. NCA at 240 min in group II subjects was significantly higher than baseline NCA (p=0.02). The serum NCAs collected before and 240 min were significantly higher in group II than in group I (p<0.05, respectively). There were no significant changes in serum histamine levels during L-ASA BPT in both groups. NCA derived from mast cell may contribute to the development of early asthmatic response induced by L-ASA inhalation. There may be a possible involvement of NCA derived from mononuclear cells during late asthmatic response.

Nonsteroidal antiinflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is characterized by moderate-to-severe asthma and a higher prevalence of chronic rhinosinusitis/nasal polyps, but is a highly heterogeneous disorder with various clinical manifestations. Two major pathogenic mechanisms are: (1) overproduction of cysteinyl leukotrienes with dysregulation of arachidonic acid metabolism and (2) increased type 2 eosinophilic inflammation affected by genetic mechanisms. Aspirin challenge is the gold standard to diagnose NERD, whereas reliable in vitro biomarkers have yet not been identified. Therapeutic approaches have been done on the basis of disease severity with the avoidance of culprit and cross-reacting NSAIDs, and when indicated, aspirin desensitization is an effective treatment option. Biologic approaches targeting Type 2 cytokines are emerging as potential therapeutic options. Here, we summarize the up-to-date evidence of pathophysiologic mechanisms and diagnosis/management approaches to the patients with NERD with its phenotypic classification. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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). Conclusions: This implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype. [ABSTRACT FROM AUTHOR]