Genetic effect of histamine N-methyltransferase (HNMT) polymorphism on chronic urticaria with aspirin hypersensitivity

BACKGROUND AND OBJECTIVE: The pathogenic mechanism of ASA (acetylsalicylic acid)-induced urticaria is still poorly understood, but it has been known that released histamine by cutaneous mast cell activation is considered to be an important role. Biogenic histamine levels are regulated by histamine synthesis enzyme, L-histidine decarboxylase (HDC), and two metabolizing enzymes, histamine N-methyltransferase (HNMT) and diamine oxidase (DAO). Especially, the presence of HNMT genetic polymorphisms might results in reduced histamine metabolism and may influence the susceptibility to develop chronic urticaria with aspirin hypersensitivity. This study investigated the histamine metabolism related gene and functional variability of the HNMT gene according to genetic polymorphisms in chronic urticaria with aspirin hypersensitivity. MATERIALS AND METHODS: We identified genetic polymorphisms in histamine metabolism related gene. Enrolled in the study were in 265 chronic urticaria (CU) patients including 111 patients with ASA intolerant chronic urticaria (AICU) compared to 154 patients with ASA tolerant chronic urticaria (ATCU), 152 normal healthy controls (NC) derived from Korean population. Four single nucleotide polymorphisms (SNPs) of HNMT and one SNP of HDC were screened using the SNP-IT and TaqMan fluorogenic 5’nuclease assay, respectively. The functional effect of polymorphisms of -465T>C, -413C>T and 939 A>G was analyzed by luciferase reporter assay, electrophoretic mobility shift assay (EMSA), 3’-UTR stability, enzyme activity assay and histamine release from basophil. RESULTS: The rare allele frequency of HNMT -465T>C polymorphism tened to be lower in CU than NC. Promoter-reporter contsruct carrying the haplotype 1 (-465T/-413C) and 2 (-465C/-413C) displayed significantly higher promoter activity than that with haplotype 3 (-465C/-413T) construct in HMC-1 cell line (p < 0.05). Transcription factor, serum response accessory protein-1 (SAP-1), was bound to the HNMT -465C allele probe (-477/-454) with higher affinity than that of the -465T allele probe. The 939A>G polymorphism was significantly associated with the AICU phenotype. The functional study using HMC-1 cells demonstrated the 939A allele had lower levels of HNMT mRNA stability, HNMT protein expression, and HNMT enzymatic activity and higher histamine release than the 939G allele. The AICU patients with the 939A allele had lower HNMT activity in RBC lysates and higher histamine release from their basophils. CONCLUSION: These results suggest that the HNMT polymorphism may be associated with HNMT activity and histamine contents on mast cell and basophils, which may contribute to the development of AICU.

Author dc:creator

• 강, 영미

Contributors dc:contributor

• 박, 해심
• 대학원 의학과
• 200424441

• Chronic urticaria
• Aspirin hypersensitivity
• HNMT
• Histamine
• Genetic polymorphism
• SAP-1
• Enzyme activity
• Basophil

Language dc:language

en

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000009126
000000009126

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/1330