A Functional Polymorphism in IL-18 Is Associated with Severity of Bronchial Asthma

Rationale IL-18 is a unique cytokine that enhances innate immunity and both Th1- and Th2-driven immune responses. Recent murine and human genetic studies have shown its role in the pathogenesis of asthma. Objectives: We conducted an association study in a Japanese population to discover variants of IL-18 that might have an effect on asthma susceptibility and/or progression and conducted functional analyses of the related variants. Methods: The IL-18 gene locus was resequenced in 48 human chromosomes. Asthma severity was determined according to the 2002 Global Initiative for Asthma Guidelines. Association and haplotype analyses were performed using 1, 172 subjects. Measurements and Main Results: Although no polymorphisms differed significantly in frequency between the control and adult asthma groups, rs.5744247 C>G was significantly associated with the severity of adult asthma (steps 1, 2 vs. steps 3, 4; P 0.0034). We also found a positive association with a haplotype (P 0.0026). By in vitro functional analyses, the rs5744247 variant was found to increase enhancer-reporter activity of the IL-18 gene in bronchial epithelial cells. Expression levels of IL-18 in response to LIPS stimulation in monocytes were significantly greater in subjects homozygous for the susceptibility G allele at rs5744247 C>G. Furthermore, we found a significant correlation between the serum IL-18 level and the genotype of rs5744247 (P = 0.031). Conclusions: Although the association results need to be replicated by other studies, IL-18 variants are significantly associated with asthma severity, and the rs5744247 variant reflects higher transcriptional activity and higher expression of IL-18 in LIPS-stimulated monocytes and a higher serum IL-18 level.