A functional promoter polymorphism of the human IL-18 gene is associated with aspirin-induced urticaria.

Background:  Urticaria is the commonest cutaneous reaction caused by aspirin or other NSAIDs. The pathogenesis of aspirin-induced urticaria (AIU) is not fully understood, but appears to involve mast cell activation and neutrophil infiltration. Objectives:  To investigate the genetic contribution of interleukin-18 (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 247 patients with AIU and 196 normal healthy controls in a Korean population. Two promoter polymorphisms of the IL-18 gene (-607A/C and -137G/C) were genotyped using the primer extension method. The functional effect of the IL-18 gene promoter polymorphism was investigated through in vitro studies including a luciferase reporter and electrophoretic mobility shift assays (EMSA) and ex vivo studies involving neutrophil chemotaxis assays. Results:  A significant association was detected between the AIU phenotype and ASA-intolerant acute urticaria (AIAU) and an IL-18 promoter polymorphism (-607A/C). Patients with AIAU showed higher frequencies of the haplotype ht1 [C(-607) G(-137) ] compared to controls (p = 0.02). Moreover, ht1 [CG] showed a high transcript haplotype by the luciferase activity assay, and EMSA 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). Conclusion:  The high transcript haplotype ht1 [CG] of the IL-18 gene may contribute to the development of acute cutaneous inflammation sensitive to aspirin, leading to the clinical presentation of AIAU.