Yu Hongsong, Luo Le, Wu Lili, Zheng Minming, Zhang Lijun, Liu Yunjia, Li Hua, Cao Qingfeng, 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.
University Eye Clinic Maastricht, Maastricht, The Netherlands.
Hum Mutat. 2015 Nov;36(11):1064-9. doi: 10.1002/humu.22829. Epub 2015 Aug 3.
Previous studies have identified that disturbed apoptosis was involved in the pathogenesis of Behçet disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome. This study aims to investigate whether copy number variations of apoptosis-related genes, including FAS, CASPASE8, CASPASE3, and BCL2, are associated with BD and VKH syndrome in Han Chinese. A two-stage association study was performed in 1,014 BD patients, 1,051 VKH syndrome patients, and 2,076 healthy controls. TaqMan(®) Copy Number Assays and real-time PCR were performed. The first-stage study showed that increased frequency of high FAS copy number (>2) was found in BD (P = 1.05 × 10(-3) ) and VKH syndrome (P = 2.56 × 10(-3) ). Replication and combined study confirmed the association of high copy number (>2) of FAS with BD (P = 3.35 × 10(-8) ) and VKH syndrome (P = 9.77 × 10(-8) ). A significant upregulated mRNA expression of FAS was observed in anti-CD3/CD28 antibodies-stimulated CD4(+) T cells from individuals carrying a high gene copy number (>2) as compared to normal diploid 2 copy number carriers (P = 0.004). Moreover, the mRNA expression of FAS both in active patients with BD and VKH syndrome was significantly higher than that in controls (P = 0.001 and P = 0.007, respectively). Our findings suggest that a high copy number of FAS gene confers risk for BD and VKH syndrome.
既往研究已证实，细胞凋亡紊乱参与了白塞病（BD）和葡萄膜大脑炎（VKH）综合征的发病机制。本研究旨在探讨包括FAS、半胱天冬酶8（CASPASE8）、半胱天冬酶3（CASPASE3）和Bcl-2在内的凋亡相关基因的拷贝数变异是否与汉族人群中的BD和VKH综合征相关。对1014例BD患者、1051例VKH综合征患者和2076例健康对照进行了两阶段关联研究。采用TaqMan®拷贝数测定法和实时定量PCR技术。第一阶段研究显示，BD患者（P = 1.05×10⁻³）和VKH综合征患者（P = 2.56×10⁻³）中FAS高拷贝数（>2）的频率增加。重复研究和联合研究证实，FAS高拷贝数（>2）与BD（P = 3.35×10⁻⁸）和VKH综合征（P = 9.77×10⁻⁸）相关。与正常二倍体2拷贝数携带者相比，携带高基因拷贝数（>2）个体的抗CD3/CD28抗体刺激的CD4⁺T细胞中，FAS的mRNA表达显著上调（P = 0.004）。此外，BD和VKH综合征活动期患者的FAS mRNA表达均显著高于对照组（分别为P = 0.001和P = 0.007）。我们的研究结果表明，FAS基因的高拷贝数赋予了BD和VKH综合征的发病风险。
