Significant Association of IL-18 Genetic Polymorphisms with Aspirin-Intolerant Urticaria in a Korean Population

INTRODUCTION: Aspirin(acetylsalicylic acid)-intolerant urticaria(AIU) aggravates urticaria after aspirin ingestion. Although the pathogenesis of AIU has not been fully understood, mast cell activation and neutrophil infiltration have been suggested to be involved. Interleukin-18 (IL-18) can stimulate mast cells and then release inflammatory mediators such as IL-4, IL-13 by stimulating mast cells. IL-18 activates neutrophils by inducing the production of TNFα, which in turn induces the synthesis of leukotriene B4. The aim of this study is to elucidate the genetic contribution of the IL-18 gene on the phathogenesis of AIU. MATERIALS AND METHODS: To perform genetic association study of IL-18 gene polymorphism with AIU, 247 patients with aspirin-intolerant urticaria (AIU) and 196 normal healthy controls(NC) were recruited from Ajou University Hospital. Two promoter polymorphisms of IL-18 gene at -607A>C and -137G>C were genotyped using a primer extension method. The functional effects of the genetic polymorphims of IL-18 were examined by luciferase reporter assay, electrophoretic mobility shift assay (EMSA) and neutrophil chemotactic assay. RESULTS: The minor allele frequency of IL-18 at -607 A>C and haplotype 1 [C-607G-137] showed significantly higher in AIAU than in NC groups(p=0.019, for AIAU vs NC; p=0.048, for AIU vs NC). The promoter-reporter construct carrying the HT1 [CG] displayed significantly higher luciferase activity than those with other haplotypes, HT2 [AG] or HT3 [AC] in two different cells including HMC-1 and Beas2B. EMSA finding showed that CREB2 bound more tightly to the -607C allele sequence than to the A allele sequence by EMSA. Moreover, subjects significantly increased neutrophil chemotaxis carrying -607C allele (p<0.001). CONCLUSION: Our findings suggest that the promoter polymorphism of IL-18 modulates IL-18 expression by altering the binding affinities of transcription factor and increasing neutrophil chemotaxis, finally contribute to the susceptibility of AIU.

Author dc:creator

• 손, 진경

Contributors dc:contributor

• 박, 해심
• 대학원 의생명과학과
• 200824662

• IL-18
• aspirin intolerant urticaria
• polymorphism
• Interleukin-18
• mast cell
• neutrophil
• aspirin
• urticariaz
• genetic polymorphism
• 인터류킨-18
• 비만세포
• 호중구
• 아스피린 과민성 두드러기
• 단일염기 다형성

Language dc:language

ko

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000010940
000000010940

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/2270