Su Guannan, Zhong Zhenyu, Zhou Qingyun, Du Liping, Ye Zi, Li Fuzhen, Zhuang Wenjuan, Wang Chaokui, Liang Liang, Ji Yan, Cao Qingfeng, Wang Qingfeng, Chang Rui, Tan Handan, Yi Shenglan, Li Yujing, Feng Xiaojie, Liao Weiting, Zhang Wanyun, Shu Jia, Tan Shiyao, Xu Jing, Pan Su, Li Hongxi, Shi Jing, Chen Zhijun, Zhu Ying, Ye Xingsheng, Tan Xiao, Zhang Jun, Liu Zhangluxi, Huang Fanfan, Yuan Gangxiang, Pang Tingting, Liu Yizong, Ding Jiadong, Gao Yingnan, Zhang Meifen, Chi Wei, Liu Xiaoli, Wang Yuqin, Chen Ling, Meguro Akira, Takeuchi Masaki, Mizuki Nobuhisa, Ohno Shigeaki, Zuo Xianbo, Kijlstra Aize, Yang Peizeng
The First Affiliated Hospital of Chongqing Medical University and Chongqing Branch of National Clinical Research Center for Ocular Diseases, Chongqing, China.
The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Arthritis Rheumatol. 2022 Apr;74(4):671-681. doi: 10.1002/art.41998. Epub 2022 Feb 14.
To explore susceptibility loci associated with uveitis in Behçet's disease (BD).
We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.
Three independent HLA alleles (HLA-B51 [3.75 × 10 ], HLA-A26 [1.50 × 10 ], and HLA-C0704 [3.44 × 10 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.
This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.
探索白塞病（BD）中与葡萄膜炎相关的易感基因座。
我们在中国人群中进行了一项两阶段研究，包括全基因组关联研究（GWAS）阶段和复制阶段。GWAS阶段纳入了978例BD相关性葡萄膜炎患者和4388例对照，复制阶段纳入了953例BD相关性葡萄膜炎患者和2129例对照。进行荧光素酶报告基因分析和染色质免疫沉淀试验，以探索ZMIZ1附近易感基因变异的功能作用。
三个独立的HLA等位基因（HLA - B51[3.75×10]、HLA - A26[1.50×10]和HLA - C0704[3.44×10]）被确定与BD相关性葡萄膜炎存在全基因组关联。在非HLA区域，除了确认7个先前报道的基因座外，我们还在16个基因座中鉴定出22个新的易感变异。对由1931例病例和6517例对照组成的中国队列与已发表的由611例病例和737例对照组成的日本队列进行的荟萃分析显示，与ZMIZ1、RPS6KA4、IL10RA、SIPA1 - FIBP - FOSL1和VAMP1存在全基因组显著关联。功能实验表明，ZMIZ1的基因变异与转录活性增强和ZMIZ1表达增加有关。
这项GWAS研究鉴定出一组与BD中葡萄膜炎易感性相关的新的基因变异。这些发现丰富了我们对遗传因素在该疾病中作用的理解。
