The CRTH2 -466T>C polymorphism increases serum and cellular eotaxin-2 production through lowered CRTH2 expression, leading to eosinophilic infiltration in AERD patients.

The HNMT 939A>G polymorphism lowers HNMT enzymatic activity by decreasing HNMT mRNA stability, which leads to an increase in the histamine level and contributes to the development of AICU.

SummaryBackground To improve understanding of aspirin hypersensitivity, this study focused on adenosine as a noncyclooxygenase target molecule of aspirin. Adenosine may affect the release of histamine from cutaneous mast cells through a mechanism mediated by the adenosine A3 receptor. Objectives To investigate the genetic contribution of adenosine A3 receptor gene (ADORA3) polymorphisms in the pathogenesis of aspirin-induced urticaria (AIU) in a case-control association study in a Korean population. Methods A case-control association study was performed in 385 patients with AIU and 213 normal controls from a Korean population. The functional variability of genetic polymorphisms in the ADORA3 gene was analysed in in vitro studies that included a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA), and ex vivo studies that included real-time polymerase chain reaction for mRNA expression in peripheral blood mononuclear cells and a histamine release assay. Results A significant association of ADORA3 promoter polymorphism at )1050G ⁄T was found with the phenotype of AIU. Patients with AIU showed higher frequency of the haplotype, ht1 (T )1050 C )564 ), compared with normal healthy controls. Moreover, ht1 (TC) was found to be a high-transcript haplotype by the luciferase activity assay, and a )564C allele-specific DNA binding protein was found by EMSA. Increased basophil histamine release was noted in subjects who had the high-transcript haplotype, ht1 (TC). Conclusion These results suggest that the high-transcript haplotype, ht1 (TC), of the ADORA3 gene may contribute to the development of cutaneous hyper-reactivity to aspirin, leading to the clinical presentation of AIU.

Our results suggest that IL-10 promoter polymorphisms contribute to the development of AIA and that rhinosinusitis may interact genetically with TGF-beta1.

SummaryBackground The thromboxane A2 receptor (TBXA2R) is a potent broncho-and vasoconstrictor and is associated with leukotriene synthesis. Polymorphisms in the TBXA2R gene have been linked to atopy, asthma, and atopic dermatitis. This study evaluated the association between genetic TBXA2R variants and the development of acetyl salicylic acid (ASA)-intolerant acute urticaria (AIAU). Methods AIAU patients (n = 167), ASA-intolerant chronic urticaria (AICU) patients (n = 149), and healthy controls (NC) (n = 265) were included. All patients were enrolled at Ajou University Hospital in Suwon, Korea. Two TBXA2R polymorphisms (À4684T4C and 795T4C) were genotyped by primer extension using a SNAPshot ddNTP primer extension kit. Luciferase activity was measured using a dual-luciferase reporter assay kit. An electrophoretic mobility shift assay (EMSA) was performed using a nuclear extract from a human mast cell line (HMC-1). Results Genetic association data demonstrated that compared with NC subjects, AIAU patients had a significantly higher frequency of the homozygous TT genotype of TBXA2R À4684T4C (P = 0.005, P corr = 0.03). No differences were identified between the AICU and the NC groups. Luciferase activity, reflecting promoter activity, was significantly lower with the TBXA2R À4684T-containing construct than with the À4684C-containing construct (Po0.001); the activity decreased further upon co-transfection with ETS-like gene transcription factor-1 (ELK-1) (P = 0.012). EMSA revealed that the À4684T allele produced a specific shifted band, with a greater affinity than that produced by the À4684C allele. Conclusion and Clinical Relevance These results suggest that the TBXA2R À4684T allele may be associated with lower TBXA2R expression, which may contribute to the development of the AIAU phenotype.