Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type 1 diabetes.
Interleukin-18 (IL-18) is a potent proinflammatory cytokine which is strongly associated with the development of diabetes in NOD mice. To test the putative involvement of IL-18 gene polymorphism in predisposition to human type 1 diabetes, the SNPs at position -607 (C/A) and -137 (G/C) in the promoter region of IL-18 gene were analyzed by sequence-specific PCR in 116 patients with type 1 diabetes and 114 normal controls. A linkage disequilibrium found only three of the four possible haplotypes defined by these SNPs. The distribution of the IL-18 gene genotypes at position -607 was significantly different between patients with type 1 diabetes and normal controls (P=0.023). Furthermore, there was a significant increase in haplotype 1 (-607C/-137G) in the patients compared with controls (P=0.006). The association study of the susceptible CTLA-4 genotype (GG at nucleotide position 49 in exon 1) or HLA-DR4-DQB1*0401 and type 1 diabetes showed that the predisposing IL-18 gene haplotype modulates the risk on CTLA-4 GG genotype, but not on HLA-DR4-DQB1*0401 haplotype. Among subjects carrying the CTLA-4 GG genotype, the frequency of IL-18 haplotype 1 in patients with type 1 diabetes was significantly higher than that in controls (91% vs. 71%, P=0.012). However, IL-18 haplotype 1 was not frequent in patients who do not exhibit the CTLA-4 high-risk genotype. These results suggest that the IL-18 gene polymorphism is associated with a type 1 diabetes susceptibility, and there might be a gene-gene interaction between IL-18 gene with susceptible CTLA-4 gene.
Ide
Akane
A
The First Department of Internal Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Kawasaki
Eiji
E
Abiru
Norio
N
Sun
Fuyan
F
Kobayashi
Masakazu
M
Fukushima
Tetsuya
T
Takahashi
Ryoko
R
Kuwahara
Hironaga
H
Kita
Atsushi
A
Oshima
Katsuya
K
Uotani
Shigeo
S
Yamasaki
Hironori
H
Yamaguchi
Yoshihiko
Y
Eguchi
Katsumi
K
D000328:Adult; D000368:Aged; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005802:Genes, MHC Class II; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics*; D007564:Japan; D008297:Male; D051379:Mice; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D020382:Interleukin-18