Significant association of FcepsilonRIalpha promoter polymorphisms with aspirin-intolerant chronic urticaria.

Abstract

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). We investigated whether genetic polymorphisms on the alpha-chain of the high-affinity IgE receptor (FcepsilonRIalpha) gene were associated with the AICU phenotype. 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. 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. 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. The FcepsilonRIalpha -344C>T polymorphism may contribute to the development of AICU.