The CGGGG Insertion/Deletion Polymorphism of the IRF5 Promoter Is a Strong Risk Factor for Primary Sjogren's Syndrome
The CGGGG Insertion/Deletion Polymorphism of the IRF5 Promoter Is a Strong Risk Factor for Primary Sjogren's Syndrome
复制标题
DOI：
10.1002/art.24662
复制
发表时间：
2009-07-01
影响因子：
--
通讯作者：
Mariette, Xavier
中科院分区：
文献类型：
--
作者：
Miceli-Richard, Corinne;Gestermann, Nicolas;Mariette, Xavier
Objective.干扰素调节因子5是参与I型干扰素（IFN）分泌的转录因子。本研究旨在探讨5-bp（CGGGG插入/缺失）启动子多态性是否与原发性干燥综合征（SS）的遗传易感性有关，并评估这种多态性的功能后果。探索性队列包括185例原发性SS患者和157例健康对照，复制队列包括200例原发性SS患者和282例健康对照。检测30例原发性SS患者外周血单个核细胞（PBMCs）和培养4周的原发性SS或干燥性涎腺上皮细胞中IRF 5 mRNA水平。在两个队列中，IRF 5 4 R CGGGG等位基因携带与原发性SS风险显著增加相关（比值比2.00 [95%置信区间1.5-2.7]，P = 6.6 x 10 - 6）。CGGGG插入/缺失多态性本身就足以解释原发性SS与IRF 5的相关性。PBMC中IRF 5 mRNA的水平显著依赖于基因型（P = 0.002），并且与IFN诱导的基因MX 1和IFITM 1的mRNA水平相关。携带4 R CGGGG IRF 5等位基因的患者的唾液腺上皮细胞培养物中IRF 5 mRNA表达水平较高（P = 0.04），其在呼肠孤病毒感染后扩增（P = 0.026）。我们的研究结果表明，协会的CGGGG插入/缺失多态性的IRF 5启动子与原发性SS。携带4 R CGGGG IRF 5等位基因的患者在PBMC和唾液腺上皮细胞中具有高水平的IRF 5 mRNA，主要是在体外病毒感染后。IRF 5 mRNA水平高的患者PBMC中I型IFN诱导基因的mRNA水平也高。
Objective. Interferon regulatory factor 5 is a transcription factor involved in type I interferon (IFN) secretion. This study was undertaken to investigate whether a 5-bp (CGGGG insertion/deletion) promoter polymorphism is involved in genetic predisposition to primary Sjogren's syndrome (SS) and to assess the functional consequences of this polymorphism.Methods. The exploratory cohort consisted of 185 patients with primary SS and 157 healthy controls, and the replication cohort consisted of 200 patients with primary SS and 282 healthy controls. Levels of IRF5 messenger RNA (mRNA) were assessed at baseline and after in vitro infection with reovirus in peripheral blood mononuclear cells (PBMCs) from 30 patients with primary SS and from salivary gland epithelial cells that had been cultured for 4 weeks from patients with primary SS or sicca symptoms.Results. Carriage of the IRF5 4R CGGGG allele was associated with a greatly increased risk of primary SS in both cohorts (odds ratio 2.00 [95% confidence interval 1.5-2.7], P = 6.6 x 10(-6)). The CGGGG insertion/deletion polymorphism alone was sufficient to explain the association of primary SS with IRF5. The level of IRF5 mRNA in PBMCs depended significantly on genotype (P = 0.002) and was correlated with the levels of mRNA for the IFN-induced genes MX1 and IFITM1. Cultured salivary gland epithelial cells from patients carrying the 4R CGGGG IRF5 allele showed a high level of IRF5 mRNA (P = 0.04), which was amplified after reovirus infection (P = 0.026).Conclusion. Our findings indicate an association of the CGGGG insertion/deletion polymorphism of the IRF5 promoter with primary SS. Patients carrying the 4R CGGGG IRF5 allele had a high level of mRNA for IRF5 in PBMCs and salivary gland epithelial cells, mainly after in vitro viral infection. Patients with high levels of mRNA for IRF5 also had high levels of mRNA for type I IFN-induced genes in PBMCs.