Harada Michishige, Obara Kazuhiko, Hirota Tomomitsu, Yoshimoto Tomohiro, Hitomi Yuki, Sakashita Masafumi, Doi Satoru, Miyatake Akihiko, Fujita Kimie, Enomoto Tadao, Taniguchi Masami, Higashi Noritaka, Fukutomi Yuma, Nakanishi Kenji, Nakamura Yusuke, Tamari Mayumi
Laboratory for Respiratory Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Am J Respir Crit Care Med. 2009 Dec 1;180(11):1048-55. doi: 10.1164/rccm.200905-0652OC. Epub 2009 Sep 10.
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.
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.
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.
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).
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.
白细胞介素-18（IL-18）是一种独特的细胞因子，可增强先天免疫以及由Th1和Th2驱动的免疫反应。最近的小鼠和人类遗传学研究表明其在哮喘发病机制中的作用。
我们在日本人群中进行了一项关联研究，以发现可能影响哮喘易感性和/或进展的IL-18变体，并对相关变体进行功能分析。
对48条人类染色体上的IL-18基因座进行重测序。根据2002年全球哮喘防治创议指南确定哮喘严重程度。对1172名受试者进行关联和单倍型分析。
尽管对照人群和成年哮喘组之间的多态性频率没有显著差异，但rs5744247 C>G与成年哮喘的严重程度显著相关（1、2级与3、4级相比；P = 0.0034）。我们还发现与一种单倍型呈正相关（P = 0.0026）。通过体外功能分析，发现rs5744247变体可增加支气管上皮细胞中IL-18基因的增强子-报告基因活性。在rs5744247 C>G位点携带易感G等位基因纯合子的受试者中，单核细胞对脂多糖刺激产生的IL-18表达水平显著更高。此外，我们发现血清IL-18水平与rs5744247的基因型之间存在显著相关性（P = 0.031）。
尽管关联研究结果需要其他研究进行重复验证，但IL-18变体与哮喘严重程度显著相关，rs5744247变体反映了脂多糖刺激的单核细胞中IL-18更高的转录活性和表达水平以及更高的血清IL-18水平。
