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Aspirin-tolerant Asthma (aspirin-tolerant + asthma)
Selected AbstractsGenetic variability in CRTH2 polymorphism increases eotaxin-2 levels in patients with aspirin exacerbated respiratory diseaseALLERGY, Issue 3 2010N. S. Palikhe To cite this article: Palikhe NS, Kim S-H, Cho B-Y, Ye Y-M, Choi G-S, Park H-S. Genetic variability in CRTH2 polymorphism increases eotaxin-2 levels in patients with aspirin exacerbated respiratory disease. Allergy 2010; 65: 338,346. Abstract Introduction:, CRTH2 is expressed on the surface of eosinophils and has been shown to mediate PGD2-induced eosinophil migration in vitro. Eosinophilic infiltration in the upper and lower airways is the key feature of asthma. Considering the fact that eosinophil infiltration is prominent in the upper and lower airways of aspirin exacerbated respiratory disease (AERD) compared to aspirin-tolerant asthma (ATA) patients, we hypothesized that activation of eosinophils via dysregulation of the CRTH2 gene may play an important role and be an important marker for AERD. Methods:, The three study groups , 107 with AERD, 115 with ATA and 133 normal healthy controls (NC) , were recruited from Ajou University Hospital, South Korea. Two polymorphisms of the CRTH2 gene at -466T>C and -129C>A were genotyped using primer extension methods. Results:, AERD patients had significantly higher serum eotaxin-2 levels than did those with ATA (P = 0.034). A significant difference in the genotype frequencies of CRTH2 -466T>C was detected between AERD and ATA patients (P < 0.05). The serum eotaxin-2 level was significantly higher in AERD patients carrying the TT genotype of CRTH2 -466T>C than those with the CT and CC (P < 0.05). In vitro functional study demonstrated that the -466T allele had lower luciferase activity (P < 0.001) and lower mRNA expression with higher production of eotaxin-2 (P = 0.003) in human lung epithelial cells. EMSA showed that CRTH2 -466T produced a specific band with a higher affinity than CRTH2 -466C had. Conclusion:, The CRTH2 -466T>C polymorphism increases serum and cellular eotaxin-2 production through lowered CRTH2 expression, leading to eosinophilic infiltration in AERD patients. [source] Alternative splicing of cyclooxygenase-1 gene: altered expression in leucocytes from patients with bronchial asthma and association with aspirin-induced 15-HETE releaseALLERGY, Issue 6 2007M. L. Kowalski Background:, Cyclooxygenase-1 (COX-1) is a key enzyme involved in generation of prostanoids, important mediators and modulators of asthmatic inflammation. In a subpopulation of aspirin-sensitive asthmatics (ASA) inhibition of COX-1 by nonsteroidal anti-inflammatory drugs results in activation of inflammatory cells and development of symptoms. Alternatively spliced variants of COX-1 lacking 111 bp from exon 9 were described previously but have never been identified in human leucocytes peripheral blood leucocytes (PBL) or upper airway epithelial cells. We aimed to assess the expression of spliced variants of COX-1 mRNA in PBLs from patients with asthma and in healthy subjects (HS) referring the expression to patients characteristics (including ASA-sensitivity) and to aspirin-triggered 15-hydroxyeicosatetraenoic acid (15-HETE) generation. Methods:, The study included 30 patients with ASA, 30 patients with aspirin-tolerant asthma (ATA) and 30 HS serving as controls. Nasal polyps for epithelial cell cultures were obtained from 10 patients with chronic rhinosinusitis. Expression of full length and spliced variants of COX-1 enzyme was detected by RT-PCR and presented as the ratio of full-length COX-1 to alternatively spliced COX-1 mRNA [COX-1 alternative splicing index (COX-1 AS index)]. Release of eicosanoids (PGE2 and 15-HETE) by PBLs was measured with enzyme immunoassay. Results:, In both PBLs and airway epithelial cells the expression of full-length product prevailed over spliced variants of COX-1 enzyme. Cyclooxygenase-1 AS index was significantly lower in asthmatics as compared to HS (1.96 ± 0.71 vs 2.41 ± 0.99, P < 0.05) indicating the relatively higher expression of the alternative transcript in asthmatic patients. Cyclooxygenase-1 AS index was not different between ASA and ATA groups (mean 1.90 ± 0.66 vs 2.02 ± 0.76, respectively, P = 0.39). There was no significant association between COX-1 AS index and mean daily dose of inhaled glucocorticosteroids or pulmonary function tests (FEV1, FVC) but in ASA group a weak correlation with daily dose of oral glucocorticosteroids was found (r = 0.39; P = 0.03). In ASA patients there was a significant positive correlation between the COX-1 AS index and the percentage of aspirin-triggered increase in 15-HETE generation (r = 0.51; P < 0.03). Conclusions:, Alternatively spliced variants of COX-1 mRNA are differently expressed in patients with bronchial asthma and may be associated with aspirin-triggered 15-HETE generation. [source] Association of SLC6A12 variants with aspirin-intolerant asthma in a Korean populationANNALS OF HUMAN GENETICS, Issue 4 2010Charisse Flerida A. Pasaje Summary Aspirin-intolerant asthma (AIA) occurs from asthma exacerbation after exposure to aspirin. However, the underlying mechanisms of AIA occurrence are still unclear. The critical role of the solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in GABAergic transmission, which is associated with mucus production in asthma, makes it a candidate gene for AIA association study. Eight single nucleotide polymorphisms (SNPs) in SLC6A12 were genotyped in 163 aspirin-intolerant asthma (AIA) and 429 aspirin-tolerant asthma (ATA) patients of Korean ethnicity. Associations between polymorphisms of SLC6A12 and AIA were analysed using multivariate logistic analysis. Results showed that two polymorphisms and a haplotype in SLC6A12, rs499368 (P= 0.005; Pcorr= 0.03), rs557881 (non-synonymous C10R, P= 0.007; Pcorr= 0.04), and SLC6A12_BL1_ht1 (P= 0.009; Pcorr= 0.05) respectively, were significantly associated with AIA after multiple testing corrections. In addition, SNPs of SLC6A12 were significantly associated with the fall rate of FEV1 by aspirin provocation suggesting that SLC6A12 could affect reversibility of lung function abnormalities in AIA patients. Although these results are preliminary and future replications are needed to confirm these findings, this study showed evidence of association between variants in SLC6A12 and AIA occurrence among asthmatics in a Korean population. [source] Association of angiotensin I-converting enzyme gene polymorphisms with aspirin intolerance in asthmaticsCLINICAL & EXPERIMENTAL ALLERGY, Issue 11 2008T-H. Kim Summary Background Aspirin-intolerant asthma (AIA) refers to the development of bronchoconstriction in asthmatic individuals following the ingestion of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). Angiotensin I-converting enzyme (ACE), a membrane-bound peptidase present in the lung, plays a pivotal role in the metabolism of the endogenous peptides involved in the pathogenesis of asthma. Methods We screened a Korean asthma cohort (581 asthmatics including 81 aspirin-intolerant asthmatics and 231 aspirin-tolerant asthmatics, and 181 normal controls) for four single nucleotide polymorphisms (SNPs; ,262 A>T and ,115 T>C in the 5,-flanking region and +5467 T>C [Pro450Pro] and+11860 A>G [Thr776Thr] in the coding region) and one ins/del (+21288 CT) in the ACE gene. Results None of the SNPs or haplotypes showed any association with the development of asthma, but they were significantly associated with the risk of AIA. Logistic regression indicated that the frequency of the rare alleles of ,262 A>T and ,115 T>C was higher in subjects with AIA than in subjects with aspirin-tolerant asthma (ATA) (P=0.003,0.01, P corr=0.015,0.05). Subjects homozygous for the rare alleles of ,262 A>T and ,115 T>C showed a greater decline in forced expiratory volume in 1 s (FEV1) after aspirin provocation than those homozygous for the common alleles (P<0.05). A luciferase reporter assay indicated that ACE promoters containing the rare ,262 A>T allele possessed lower activity than did those containing the common allele (P=0.009). In addition, ACE promoters bearing the rare ,115 T>C allele had no luciferase activity. DNA,protein binding assays revealed a band containing the ACE promoter region (including ,262 A) and a protein complex. Conclusion The ,262 A>T polymorphism in the promoter of the ACE gene is associated with AIA, and the rare allele of ,262 A>T may confer aspirin hypersensitivity via the down-regulation of ACE expression. [source] | ||||||||||