The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing, China.
Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):1158-1166. doi: 10.1167/iovs.17-23247.
Long noncoding RNAs (lncRNAs) are emerging as important regulators of inflammatory immune responses, whereby genetic variants may affect this biologic function. This study aimed to investigate the association of 110 single nucleotide polymorphisms (SNPs) of lncRNAs, known to be associated with autoimmune disease, in patients with ocular Vogt-Koyanagi-Harada (VKH) disease, Behcet's disease (BD), and acute anterior uveitis (AAU) with or without ankylosing spondylitis (AS).
A two-stage case-control study was performed on 1626 VKH patients, 384 BD patients, 624 AAU with AS, 751 AAU without AS, 720 AS without AAU, and 3305 healthy subjects. lncRNAs 110 SNPs were genotyped using MassARRAY System or TaqMan SNP assays. The gene expression and cytokine production were measured using real-time PCR or ELISA.
The frequency of the C allele of rs4937362 in RP11-264E20.1 was markedly decreased in the AS without AAU group compared with controls (Combined P = 9.37 × 10-7, odds ratio [OR] = 0.73). An increased frequency of the A allele of rs6871626 between UBLCP1, IL12B, and LOC285627 was found in VKH patients compared with controls (Combined P = 1.88 × 10-4, OR = 1.19). UBLCP1, IL12B, and LOC285627 were expressed in human uveal tissues. Functional studies showed a decreased LOC285627 mRNA expression in peripheral blood mononuclear cells (PBMCs) and an increased IL-10 production in PBMCs following LPS stimulation in rs6871626 CC genotype carriers.
Our study is the first to show that rs4937362/RP11-264E20.1 is associated with AS and that rs6871626 is associated with VKH disease in Chinese Han. The protective rs6871626 genotype was shown to regulate the expression of LOC285627 and to increase the production of the anti-inflammatory cytokine IL-10.
长链非编码 RNA（lncRNA）正在成为炎症免疫反应的重要调节因子，遗传变异可能影响这种生物学功能。本研究旨在探讨已知与自身免疫性疾病相关的 110 个 lncRNA 单核苷酸多态性（SNP）与眼部 Vogt-Koyanagi-Harada（VKH）病、Behcet 病（BD）和急性前葡萄膜炎（AAU）患者的关联，这些患者伴或不伴有强直性脊柱炎（AS）。
采用两阶段病例对照研究，纳入 1626 例 VKH 患者、384 例 BD 患者、624 例 AAU 伴 AS、751 例 AAU 不伴 AS、720 例 AS 不伴 AAU 及 3305 例健康对照者。采用 MassARRAY 系统或 TaqMan SNP 检测试剂盒对 110 个 lncRNA SNP 进行基因分型。采用实时 PCR 或 ELISA 检测基因表达和细胞因子产生情况。
与对照组相比，AS 不伴 AAU 组 rs4937362 位于 RP11-264E20.1 上的 C 等位基因频率明显降低（合并 P=9.37×10-7，优势比[OR]=0.73）。与对照组相比，VKH 患者 UBLCP1、IL12B 和 LOC285627 之间 rs6871626 的 A 等位基因频率升高（合并 P=1.88×10-4，OR=1.19）。UBLCP1、IL12B 和 LOC285627 在人眼葡萄膜组织中表达。功能研究显示，rs6871626 CC 基因型携带者外周血单个核细胞（PBMCs）中 LOC285627 mRNA 表达降低，脂多糖刺激后 PBMCs 中 IL-10 产生增加。
本研究首次表明，rs4937362/RP11-264E20.1 与 AS 相关，rs6871626 与中国汉族 VKH 病相关。保护性 rs6871626 基因型可调节 LOC285627 的表达，并增加抗炎细胞因子 IL-10 的产生。
