title: A functional promoter polymorphism of the human IL18 gene is associated with aspirin-induced urticaria.
abstract: BACKGROUND
  Urticaria is the commonest cutaneous reaction caused by aspirin or other nonsteroidal anti-inflammatory drugs. The pathogenesis of aspirin-induced urticaria (AIU) is not fully understood, but appears to involve mast cell activation and neutrophil infiltration.
  
  
  OBJECTIVE
  To investigate the genetic contribution of interleukin (IL)-18, which can amplify acute inflammation by promoting mast cell activation, neutrophil migration and cytokine production, to the pathogenesis of AIU.
  
  
  METHODS
  A case-control association study was performed using 275 patients with AIU and 196 normal healthy controls in a Korean population. Two promoter polymorphisms of the IL18 gene (-607A/C and -137G/C) were genotyped using the primer extension method. The functional effect of the IL18 gene promoter polymorphism was investigated through in vitro studies including a luciferase reporter assay and electrophoretic mobility shift assays (EMSAs) and ex vivo studies involving neutrophil chemotaxis assays.
  
  
  RESULTS
  A significant association was detected between both AIU in general and the aspirin-intolerant acute urticaria (AIAU) phenotype and the IL18 promoter polymorphism -607A/C. Patients with AIAU showed higher frequencies of the C(-607) G(-137) haplotype, ht1 [CG], compared with controls (P=0·02). Moreover, ht1 [CG] showed a high transcript haplotype by the luciferase activity assay, and EMSAs identified a -607C allele-specific DNA-binding protein as CREB2. Neutrophil chemotactic activity was highest in subjects with AIU exhibiting the high transcript haplotype, ht1 [CG] (P=0·019).
  
  
  CONCLUSIONS
  The high transcript haplotype ht1 [CG] of the IL18 gene may contribute to the development of acute cutaneous inflammation sensitive to aspirin, leading to the clinical presentation of AIAU.
authors.affiliation: Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Youngtonggu, Suwon 442-721, Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Kim
authors.forename: J K
authors.initials: JK
authors.lastname: Son
authors.forename: E-M
authors.initials: EM
authors.lastname: Yang
authors.forename: J-E
authors.initials: JE
authors.lastname: Kim
authors.forename: H-S
authors.initials: HS
authors.lastname: Park
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001241:Aspirin / Q000009:adverse effects*; D016022:Case-Control Studies; D002465:Cell Movement / Q000235:genetics; D003875:Drug Eruptions / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D020298:U937 Cells; D014581:Urticaria / Q000139:chemically induced* / Q000235:genetics*; D055815:Young Adult
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D020382:Interleukin-18; D001241:Aspirin