Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus
Comprehensive evaluation of the genetic variants of interferon regulatory factor 5 (IRF5) reveals a novel 5 bp length polymorphism as strong risk factor for systemic lupus erythematosus
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DOI：
10.1093/hmg/ddm359
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发表时间：
2008-03-15
影响因子：
3.5
通讯作者：
Syvaenen, Ann-Christine
中科院分区：
文献类型：
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作者：
Sigurdsson, Snaevar;Goering, Harald H. H.;Syvaenen, Ann-Christine
我们在485名瑞典患者和563名对照者中分析了干扰素调节因子5（IRF 5）基因单核苷酸多态性（SNP）和长度多态性与自身免疫性疾病系统性红斑狼疮（SLE）的关系。共发现16个SNPs和2个长度多态性与SLE相关（P < 0.0005，OR > 1.4）。使用贝叶斯模型选择和平均方法，我们确定了简约的模型，正好有两个独立的与SLE相关的IRF 5的变体。在SLE中具有最高后验概率（分别为1.00和0.71）的IRF 5变体是位于IRF 5 3'的SNP（rs 10488631）和位于IRF 5第一个非翻译外显子（外显子1A）上游64 bp的新型CGGGG插入-缺失（indel）多态性。CGGGG indel解释了IRF 5基因中多个SNP的关联信号，包括rs 2004640、rs 10954213和rs729302，这些先前被认为是SLE的致病变异。CGGGG插入缺失包含序列CGGGG的三个或四个重复，其中较长的等位基因包含作为SLE的风险等位基因的另外的SPl结合位点。使用电泳迁移率变动分析，我们显示增加的结合蛋白质的风险等位基因的CGGGG插入缺失，并使用小基因报告基因分析，我们显示增加的表达IRF 5 mRNA从启动子含有该等位基因。在携带CGGGG插入缺失风险等位基因的SLE患者外周血单个核细胞中观察到IRF 5蛋白表达增加。我们已经发现，相同的IRF 5等位基因也赋予炎症性肠病和多发性硬化症的风险，这表明IRF 5在自身免疫性疾病中的一般作用。
We analyzed a comprehensive set of single-nucleotide polymorphisms (SNPs) and length polymorphisms in the interferon regulatory factor 5 (IRF5) gene for their association with the autoimmune disease systemic lupus erythematosus (SLE) in 485 Swedish patients and 563 controls. We found 16 SNPs and two length polymorphisms that display association with SLE (P < 0.0005, OR > 1.4). Using a Bayesian model selection and averaging approach we identified parsimonious models with exactly two variants of IRF5 that are independently associated with SLE. The variants of IRF5 with the highest posterior probabilities (1.00 and 0.71, respectively) of being causal in SLE are a SNP (rs10488631) located 3' of IRF5, and a novel CGGGG insertion-deletion (indel) polymorphism located 64 bp upstream of the first untranslated exon (exon 1A) of IRF5. The CGGGG indel explains the association signal from multiple SNPs in the IRF5 gene, including rs2004640, rs10954213 and rs729302 previously considered to be causal variants in SLE. The CGGGG indel contains three or four repeats of the sequence CGGGG with the longer allele containing an additional SP1 binding site as the risk allele for SLE. Using electrophoretic mobility shift assays we show increased binding of protein to the risk allele of the CGGGG indel and using a minigene reporter assay we show increased expression of IRF5 mRNA from a promoter containing this allele. Increased expression of IRF5 protein was observed in peripheral blood mononuclear cells from SLE patients carrying the risk allele of the CGGGG indel. We have found that the same IRF5 allele also confers risk for inflammatory bowel diseases and multiple sclerosis, suggesting a general role for IRF5 in autoimmune diseases.