Jiang Yanni, Wang Hong, Yu Hongsong, Li Lin, Xu Dengfeng, Hou Shengping, Kijlstra Aize, Yang Peizeng
The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, P R China.
Beijing Tongren Eye Center, Beijing Key Laboratory of Ophthalmology and Visual Science, Beijing Tongren Hospital, Capital Medical University, Beijing, P R China.
Sci Rep. 2016 Jan 22;6:19651. doi: 10.1038/srep19651.
Several modulatory factors in the TLR signaling pathway including IRF3, IRF7, IRF8, TRIM20, MYD88 and NF-κB1 have been associated with autoimmune disease. In this study, we investigated the association of 13 SNPs for these genes with Behçet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Haplotype and linkage disequilibrium (LD) analysis were performed by Haploview4.2. IRF8 mRNA expression and cytokine production was tested by real-time PCR and ELISA. Two SNPs near IRF8 were associated with BD (for rs17445836 GG genotype, Pc = 9.56 × 10(-8), OR = 2.044; for rs11642873 AA genotype, Pc = 9.24 × 10(-7), OR = 1.776). No significant association was found for the 13 SNPs tested with VKH syndrome. Haplotype analysis of the two positive SNPs revealed that the AG haplotype was significantly increased in BD patients (Pc = 2.60 × 10(-8), OR = 1.646). Functional studies revealed an increased mRNA expression of IRF8 and IFN-γ production and a decreased production of IL-10 in rs17445836 carriers with the GG genotype. Increased expression of IRF8 as well as IFN-γ production and a decreased production of IL-10 were found in individuals carrying the rs11642873/AA genotype. In conclusion, this study indicates that IRF8 may contribute to the genetic susceptibility of BD by regulating IRF8 expression and cytokine production.
Toll样受体（TLR）信号通路中的几种调节因子，包括干扰素调节因子3（IRF3）、干扰素调节因子7（IRF7）、干扰素调节因子8（IRF8）、三结构域蛋白20（TRIM20）、髓样分化因子88（MYD88）和核因子κB1（NF-κB1），都与自身免疫性疾病有关。在本研究中，我们使用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析法，研究了这些基因的13个单核苷酸多态性（SNP）与白塞病（BD）和Vogt-小柳-原田（VKH）综合征的相关性。通过Haploview4.2进行单倍型和连锁不平衡（LD）分析。通过实时PCR和酶联免疫吸附测定（ELISA）检测IRF8信使核糖核酸（mRNA）表达和细胞因子产生情况。IRF8附近的两个SNP与BD相关（对于rs17445836的GG基因型，校正P值（Pc）=9.56×10⁻⁸，比值比（OR）=2.044；对于rs11642873的AA基因型，Pc=9.24×10⁻⁷，OR=1.776）。在所检测的13个SNP中，未发现与VKH综合征有显著相关性。对两个阳性SNP的单倍型分析显示，BD患者中AG单倍型显著增加（Pc=2.60×10⁻⁸，OR=1.646）。功能研究显示，携带rs17445836/GG基因型的个体中，IRF8的mRNA表达增加、γ干扰素（IFN-γ）产生增加，白细胞介素10（IL-10）产生减少。在携带rs11642873/AA基因型的个体中，发现IRF8表达以及IFN-γ产生增加，IL-10产生减少。总之，本研究表明，IRF8可能通过调节IRF8表达和细胞因子产生，导致BD的遗传易感性。
