Significant association of Fc epsilon RI alpha promoter polymorphisms with aspirin-intolerant chronic urticaria

Abstract

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 a-chain of the high-affinity IgE receptor (Fc epsilon RI alpha) gene were associated with the AICU phenotype. Methods: We genotyped 2 promoter polymorphisms (-344C > T and -95T > C) of Fc epsilon RI alpha 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 Fc epsilon RI alpha promoter may be associated with increased expression of Fc epsilon RI alpha on mast cells and enhanced release of histamine. Clinical implications: The Fc epsilon RI alpha -344C > T polymorphism may contribute to the development of AICU.