Akahoshi M, Nakashima H, Sadanaga A, Miyake K, Obara K, Tamari M, Hirota T, Matsuda A, Shirakawa T
Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan.
Lupus. 2008 Jun;17(6):568-74. doi: 10.1177/0961203308089340.
In order to identify a novel candidate gene in systemic lupus erythematosus (SLE), we analysed a panel of six genes encoding molecules involved in the type I interferon (IFN) system. We first identified variants in the five genes related to type I IFN pathway by sequencing. Genotyping of a panel of eight selected single-nucleotide polymorphisms (SNPs) in six candidate genes (TLR9, MYD88, IRF3, IRF7, IFNB1, IFNA17) was performed in 137 patients with SLE and matched with 152 healthy controls using polymerase chain reaction-restriction fragment length polymorphism analysis. In functional assay, quantitative real-time polymerase chain reaction was performed to assess constitutive IRF3 mRNA expression in peripheral blood mononuclear cells from healthy subjects with different IRF3 promoter haplotypes. Among eight SNPs genotyped, an IRF3 SNP at -925 was found to be associated with SLE after correction for multiple tests (corrected P=0.016). Of total five IRF3 SNPs genotyped, the promoter IRF3 SNPs -925A/G and -776C/T showed the most significant association with SLE. With regard to -925A/G, the frequency of GG genotype was significantly decreased among SLE patients compared with the control group (1.5% vs. 9.9%; chi(2)=10.0, P=0.0015, odds ratio 0.12, 95% confidence interval 0.027-0.554). Our experimental data indicated that constitutive IRF3 mRNA expression was significantly lower in cells carrying the minor G-T/G-T haplotype pair compared with those carrying the major A-C haplotype. In conclusion, we showed that the promoter SNPs of the IRF3 gene were significantly associated with resistance against SLE.
为了鉴定系统性红斑狼疮（SLE）中的一个新候选基因，我们分析了一组六个编码参与I型干扰素（IFN）系统分子的基因。我们首先通过测序在与I型IFN途径相关的五个基因中鉴定出变异。对六个候选基因（TLR9、MYD88、IRF3、IRF7、IFNB1、IFNA17）中的一组八个选定单核苷酸多态性（SNP）进行基因分型，共纳入137例SLE患者，并使用聚合酶链反应-限制性片段长度多态性分析与152名健康对照进行匹配。在功能测定中，进行定量实时聚合酶链反应以评估来自具有不同IRF3启动子单倍型的健康受试者外周血单个核细胞中组成型IRF3 mRNA的表达。在基因分型的八个SNP中，经过多重检验校正后发现-925位点的一个IRF3 SNP与SLE相关（校正P = 0.016）。在总共五个基因分型的IRF3 SNP中，启动子IRF3 SNP -925A/G和-776C/T与SLE的关联最为显著。关于-925A/G，与对照组相比，SLE患者中GG基因型的频率显著降低（1.5%对9.9%；χ² = 10.0，P = 0.0015，优势比0.12，95%置信区间0.027 - 0.554）。我们的实验数据表明，与携带主要A-C单倍型的细胞相比，携带次要G-T/G-T单倍型对的细胞中组成型IRF3 mRNA表达显著降低。总之，我们表明IRF3基因的启动子SNP与SLE抗性显著相关。
