Association of thromboxane A2 receptor (TBXA2R) gene polymorphism in patients with aspirin‐intolerant acute urticaria

Abstract

The thromboxane A2 receptor (TBXA2R) is a potent broncho- and vaso-constrictor 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). 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 (-4684T>C and 795T>C) 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). Genetic association data demonstrated that compared with NC subjects, AIAU patients had a significantly higher frequency of the homozygous TT genotype of TBXA2R-4684T>C (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-4684T-containing construct than with the -4684C-containing construct (P<0.001); the activity decreased further upon co-transfection with ETS-like gene transcription factor-1 (ELK-1) (P=0.012). EMSA revealed that the -4684T allele produced a specific shifted band, with a greater affinity than that produced by the -4684C allele. These results suggest that the TBXA2R-4684T allele may be associated with lower TBXA2R expression, which may contribute to the development of the AIAU phenotype.