A functional polymorphism in IL-18 is associated with severity of bronchial asthma.
BACKGROUND
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.


OBJECTIVE
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.


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.
Harada
Michishige
M
Laboratory for Respiratory Diseases, Center for Genomic Medicine, Institute of Physical and Chemical Research (RIKEN, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
Obara
Kazuhiko
K
Hirota
Tomomitsu
T
Yoshimoto
Tomohiro
T
Hitomi
Yuki
Y
Sakashita
Masafumi
M
Doi
Satoru
S
Miyatake
Akihiko
A
Fujita
Kimie
K
Enomoto
Tadao
T
Taniguchi
Masami
M
Higashi
Noritaka
N
Fukutomi
Yuma
Y
Nakanishi
Kenji
K
Nakamura
Yusuke
Y
Tamari
Mayumi
M
D000328:Adult; D000368:Aged; D001249:Asthma / Q000097:blood / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D055815:Young Adult
D020382:Interleukin-18