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.

中文翻译：

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日本1型糖尿病患者IL-18基因启动子多态性与CTLA-4基因49A / G多态性之间的关联。

白介素-18（IL-18）是一种有效的促炎细胞因子，与NOD小鼠中的糖尿病发展密切相关。为了测试IL-18基因多态性在人1型糖尿病易感性中的可能参与性，通过如下方法分析了IL-18基因启动子区域中-607（C / A）和-137（G / C）的SNP。 116位1型糖尿病患者和114位正常对照的序列特异性PCR。连锁不平衡仅发现这些SNP定义的四种可能的单倍型中的三种。在1型糖尿病患者和正常对照组之间，IL-18基因基因型在-607位置的分布有显着差异（P = 0.023）。此外，与对照组相比，患者的单倍型1（-607C / -137G）显着增加（P = 0.006）。对易感CTLA-4基因型（外显子1的49位核苷酸的GG）或HLA-DR4-DQB1 * 0401与1型糖尿病的关联研究表明，易患的IL-18基因单倍型调节了CTLA-4 GG基因型的风险，但不适用于HLA-DR4-DQB1 * 0401单倍型。在携带CTLA-4 GG基因型的受试者中，1型糖尿病患者的IL-18单倍型1频率显着高于对照组（91％比71％，P = 0.012）。但是，IL-18单倍型1在没有表现出CTLA-4高风险基因型的患者中并不常见。这些结果表明IL-18基因多态性与1型糖尿病易感性有关，并且IL-18基因与易感CTLA-4基因之间可能存在基因-基因相互作用。