Polymorphisms of High-affinity IgE Receptor Genes in Patients with Aspirin-Intolerant Chronic Urticaria

BACKGROUND AND OBJECTIVE: Chronic urticaria is commonly associated with aspirin hypersensitivity. 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). Atopy was reported a risk factor for a patient with AICU and approximately 40% of patients with chronic urticaria have autoimmune urticaria. The high-affinity receptor for IgE (FcεRI) expressed on mast cells and basophils plays a critical role in mediating allergic reactions induced by antigen-specific IgE antibody bindings. FcεRI is composed of three subunits: the IgE-binding α-chain, a signal-augmenting β-chain, and a signal-transducing γ-chain dimer. This study was aimed to evaluate whether six polymorphisms of three subunit genes (FcεRIα, FcεRIβ and FcεRIγ) of FcεRI were associated with the AICU phenotype. MATERIALS AND METHODS: We genotyped six polymorphisms, FcεRIα -344C>T, FcεRIα -95T>C, FcεRIβ -109T>C, FcεRIβ E237G, FcεRIγ 237A>G and FcεRIγ -54G>T, of three subunit genes of FcεRI in 116 patients with ASA intolerant chronic urticaria (AICU) compared to 155 patients with ASA tolerant chronic urticaria (ATCU) and 222 normal healthy controls (NC) derived from a Korean population. The functional effect of polymorphisms of FcεRIα -344C>T and FcεRIβ -109T>C was analyzed by luciferase reporter assay and electrophoretic mobility shift assay. RESULTS: The rare allele frequency of FcεRIα -344C>T polymorphism was significantly higher in AICU group than those of other control groups (p = 0.008, for AICU vs. ATCU; p = 0.030, for AICU vs. NC). This polymorphism was also significantly associated with the serum total IgE level (p = 0.010) within AICU patients. The frequency of FcεRIα -95C allele was also significantly higher in AICU (6.3%) than ATCU (1.7%) (p = 0.021) but no significant difference in allele and genotype frequencies were noted between AICU and NC. Reporter plasmid carrying the FcεRIα -344T allele displayed significantly higher promoter activity than that with the -344C allele in RBL-2H3 cell line (p < 0.001). Transcription factor Myc-associated zinc finger protein (MAZ) was bound to the FcεRIα -344C allele probe (-354/-334) with the higher affinity than that of the -344T allele probe. There were no significant differences in allele and genotype frequencies, and haplotype frequencies of two SNPs of FcεRIβ among the three groups (p > 0.05, respectively). However, the polymorphism of FcεRIβ E237G was significantly associated with the higher rate of atopy (p = 0.032) in AICU patients. Reporter plasmid carrying the FcεRIβ -109T allele displayed significantly higher promoter activity than that with the -109C allele in both RBL-2H3 and A549 cell lines. In addition, we found that a specific DNA- protein complex with higher affinity was detected in -109T allele probe compared in -109C probe, but a transcription factor which binds to -109T allele probe was not identified. In two SNPs of FcεRIγ, no significant differences were observed in allele and genotype frequencies, and haplotype frequencies among the three groups (p > 0.05, respectively). However, the polymorphism of FcεRIγ -237A>G was significantly associated with a higher rate of atopy in AICU patients (p = 0.039) and the polymorphism of FcεRIγ -54T>C was significantly associated with the prevalence of anti-thyroglobulin antibody (p = 0.011) in AICU patients. When the effect of the FcεRI polymorphisms on the histamine releasability of peripheral blood basophils from AICU patients was analyzed, the histamine releasability of the patients carrying heterozygous CT of FcεRIα -344C>T was found to be higher than that of the the patients carrying homozygous CC of FcεRIα -344C>T (p = 0.045). CONCLUSION: These results suggest that the FcεRIα -344C>T polymorphism of the FcεRIα promoter may be associated with increased expression of FcεRIα on mast cells enhanced release of histamine, which may contribute to the development of AICU. In addition, polymorphisms of FcεRIβ E237G and FcεRIγ -237A>G may be associated with the susceptibility of AICU.

Author dc:creator

• 배, 진식

Contributors dc:contributor

• 박, 해심
• 대학원 의학과
• 200424314

• Chronic urticaria
• aspirin hypersensitivity
• high affinity IgE receptor
• genetic polymorphism
• IgE

Language dc:language

en

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000002049
000000002049

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/1290