综合征基因多态性

中国汉族人群中白塞氏病和VKH综合征与ATG基因有关

【据《InvestigativeOphthalmology&VisualScience》2015年1...

【据《Investigative Ophthalmology & Visual Science》2015年12月报道】题：中国汉族人群中ATG5基因多态性与Behcet综合征的关系以及ATG10基因多态性与VKH综合征的关系（英文题：Association of ATG5 Gene Polymorphisms With Behcet’s Disease and ATG10 Gene Polymorphisms With VKH Syndrome in a Chinese Han Population；作者：杨培增等；单位：重庆医科大学附属第一医院眼科）

葡萄膜炎是一种常见的致盲眼病。白塞氏病（Behcet’s disease，BD）和小柳原田综合征（VKH）是亚洲常见的两种葡萄膜炎综合征。以往研究显示Th1和Th17细胞反应在这两类疾病的发病机理中起关键作用。而近期研究表明自噬相关基因（autophagy-related genes，ATGs）遗传变异性在多种自身免疫性疾病（如系统性红斑狼疮、克罗恩病、银屑病等）发展的诱因中起一定作用。然而迄今为止ATGs和葡萄膜炎的关系尚未证实。杨培增教授团队通过本实验研究中国汉族人群中自噬相关基因单核苷酸多态（SNPs）与白塞氏综合征、小柳原田综合征的关联性。

杨教授团队在940名BD患者、1061名VKH患者、2007名正常人群中开展二阶段关联研究。自噬家族10种基因（ATG5、ATG7、ATG10、ATG16L1、IRGM、LKKR2、ATG2A、DAP、ULK1、TSC1）遗传变异性用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）或者TaqMan SNP方法进行基因分型。研究结果表明，在BD患者中rs573775/ATG5位点的TT型降低其易感性（Pc = 8.35×10-6，OR=0.490）。在VKH患者中，rs4703863/ATG10位点的AC型增加其易感性（Pc = 9.94×10-5，OR=1.444），而rs4703863的A等位基因和AA型可作为其保护因子（Pc = 7.06×10-5，OR=0.745；Pc = 6.34×10-6，OR=0.669）。功能性实验显示rs573775位点的TT型中内毒素刺激后的外周血单个核细胞（PBMCs）ATG5水平高于对照组。发病期且未接受免疫抑制治疗的BD患者ATG5mRNA水平明显高于正常对照组。

杨教授总结，该研究显示中国汉族人群中ATG5基因rs573775位点与白塞氏综合征相关，而ATG10基因rs4703863位点与小柳原田综合征相关。此外，ATG5基因变异被证实与ATG5表达相关。

Abstract

PURPOSE:

This study was conducted to explore the association of autophagy-related genes (ATGs) single nucleotide polymorphisms (SNPs) with Behçet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome in a Chinese Han population.

METHODS:

A two-stage association study was carried out in 940 BD, 1061 VKH, and 2007 healthy controls. Genotyping for genetic variants of 10 autophagy family genes (ATG5, ATG7, ATG10, ATG16L1, IRGM, LKKR2, ATG2A, DAP, ULK1, and TSC1) was performed using PCR-restriction fragment length polymorphism (PCR-RFLP) or TaqMan SNP assays. Gene expression was quantified by real-time PCR.

RESULTS:

In the cohort of BD patients, we observed that the TT genotype of rs573775/ATG5 decreased susceptibility to BD (Pc = 8.35 × 10-6, OR = 0.490). In the case of VKH patients, the AC genotype of rs4703863/ATG10 increased susceptibility to VKH syndrome (Pc = 9.94 × 10-5, OR = 1.444), whereas the A allele and AA genotype of rs4703863 (Pc = 7.06 × 10-5, OR = 0.745; Pc = 6.34 × 10-6, OR = 0.669, respectively) acted as protective factors for VKH. Functional experiments showed an increased ATG5 expression by LPS stimulated PBMCs in TT cases of rs573775 compared with controls. The level of ATG5 mRNA in active BD patients not receiving immunosuppression was significantly higher than that in healthy controls.

CONCLUSIONS:

This study demonstrated an association of ATG5 rs573775 with BD and ATG10 rs4703863 with VKH syndrome in a Chinese Han population. Furthermore, a variant of the ATG5 gene was shown to be correlated with ATG5 expression.

（程丹报道）