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

¹ Laboratory for Respiratory Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Kanagawa; ² Hitachi Chemical Co., Ltd., Hitachi, Ibaraki; ³ Department of Immunology and Medical Zoology, Hyogo College of Medicine, Hyogo; ⁴ Department of Pediatric Allergy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Osaka; ⁵ Miyatake Asthma Clinic, Osaka; ⁶ School of Human Nursing, The University of Shiga Prefecture, Shiga; ⁷ NPO Japan Health Promotion Supporting Network, Wakayama; ⁸ Clinical Research Center, National Hospital Organization, Sagamihara National Hospital, Kanagawa; and ⁹ Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Mayumi Tamari, M.D., Ph.D., Laboratory for Respiratory Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN); 1-7-22 Suehiro, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. E-mail: tamari{at}src.riken.jp

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, rs5744247 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 LPS 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 LPS-stimulated monocytes and a higher serum IL-18 level.

Key Words: asthma severity • IL-18 • LPS • monocytes • genetic polymorphisms

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject IL-18 plays multiple roles in chronic inflammation and in a number of infections and enhances both Th1- and Th2-mediated immune responses. The influence of genetic changes in this crucial cytokine on the etiology of asthma is unclear. What This Study Adds to the Field Our results suggest that a functionally relevant IL-18 polymorphism contributes to the disease severity of asthma. The variant affects the level of mRNA expression induced by LPS in human monocytes and correlates with the serum IL-18 level in individuals with asthma. The LPS-induced IL-18 expression was not suppressed by dexamethasone and salmeterol.

 

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