Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type I diabetes
Association between IL-18 gene promoter polymorphisms and CTLA-4 gene 49A/G polymorphism in Japanese patients with type I diabetes
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DOI：
10.1016/j.jaut.2003.10.001
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发表时间：
2004-02-01
影响因子：
12.8
通讯作者：
Eguchi, K
中科院分区：
文献类型：
--
作者：
Ide, A;Kawasaki, E;Eguchi, K
白介素18(IL-18)是一种强有力的促炎细胞因子，与NOD小鼠糖尿病的发生发展密切相关。为探讨IL-18基因多态性与I型糖尿病易感性的关系，采用序列特异性聚合酶链式反应(SNP)技术，对116例I型糖尿病患者和114例正常对照的IL-18基因启动子区-607(C/A)和-137(G/C)位的SNPs进行了分析。连锁不平衡只发现了这些SNPs定义的四种可能的单倍型中的三种。I型糖尿病患者IL-18基因-607位点的分布与正常对照组比较差异有统计学意义(P=0.023)。患者组单倍型I(-6070-137G)频率显著高于对照组(P=0.006)。易感CTLA-4基因(外显子1第49位GG)或人类白细胞抗原-DR4-DQB1*0401与I型糖尿病的关联研究表明，易感IL-18基因单倍型调节CTLA-4 GG基因型的风险，但不调节单倍型的风险。在携带CTLA-4GG基因的受试者中，I型糖尿病患者IL-18单倍型1的频率显著高于对照组(91%vs.71%，P=0.012)。然而，在没有CTLA-4高危基因的患者中，IL-18单倍型I并不常见。提示IL-18基因多态性与I型糖尿病易感性有关，IL-18基因与易感CTLA-4基因之间可能存在基因-基因交互作用。(C)2003爱思唯尔有限公司。保留所有权利。
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 I 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 I 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 I diabetes and normal controls (P=0.023). Furthermore, there was a significant increase in haplotype I (-6070-137G) 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 I 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 I diabetes was significantly higher than that in controls (91% vs. 71%, P=0.012). However, IL-18 haplotype I 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 I diabetes susceptibility, and there might be a gene-gene interaction between IL-18 gene with susceptible CTLA-4 gene. (C) 2003 Elsevier Ltd. All rights reserved.