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首页> 外文期刊>Arthritis & Rheumatism >Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus
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Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus

机译：遗传变异和疾病相关因素有助于系统性红斑狼疮患者血细胞中干扰素调节因子5表达的增强

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ObjectiveGenetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients.MethodsIRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype.ResultsIRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression.ConclusionThis study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE.
机译：目的干扰素（IFN）调节因子5基因（IRF5）的遗传变异与系统性红斑狼疮（SLE）的易感性有关。这些变体对SLE患者原代血细胞中IRF-5表达的贡献尚未得到解决，I型IFN也没有作用。这项研究的目的是确定SLE患者中IRF-5表达增加与IRF5风险单倍型之间的相关性。方法采用实时荧光定量PCR检测44例瑞典SLE患者和16个健康对照者的IRF-5转录水平和蛋白质水平连锁反应，小基因测定和流式细胞仪。在这些患者中，对单核苷酸多态性rs2004640，rs10954213和rs10488631以及CGGGG插入/缺失进行了基因分型。这些多态性的基因型定义了常见的危险单倍型和保护性单倍型。结果与健康供体相比，SLE患者的IRF-5表达和选择性剪接显着上调。转录和蛋白质水平的提高与IRF5的风险单倍型相关。 rs10488631显示了唯一重要的独立关联，该关联与来自非编码第一外显子1C的转录增加相关。 Minigene实验证明了rs2004640和CGGGG的插入/缺失以及I型IFN在调节IRF5表达中的重要作用。结论本研究首次正式证明IRF-5表达和其他剪接在原代血细胞中显着上调SLE患者。此外，危险单倍型与SLE患者IRF-5转录和蛋白表达增强有关。

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