Promoter polymorphisms in the IRF3 gene confer protection against systemic lupus erythematosus

Lupus - Tập 17 Số 6 - Trang 568-574 - 2008
Mitsuteru Akahoshi1, Hitoshi Nakashima2, Atsushi Sadanaga2, Katsuhisa Miyake2, Kazuhiko Obara3, Mayumi Tamari3, Tomomitsu Hirota3, Akira Matsuda3, Taro Shirakawa3
1Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan; Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Chihaya Hospital, Fukuoka, Japan
2Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
3Laboratory for Genetics of Allergic Diseases, SNP Research Center, RIKEN Yokohama Institute, The Institute of Physical and Chemical Research (RIKEN), Yokohama, Japan

Tóm tắt

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%; χ2 = 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.

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Lupus

Tập 17 Số 6

568-574

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