Hou Shengping, Yang Zhenglin, Du Liping, Jiang Zhengxuan, Shu Qinmeng, Chen Yuanyuan, Li Fuzhen, Zhou Qingyun, Ohno Shigeaki, Chen Rui, Kijlstra Aize, Rosenbaum James T, Yang Peizeng
The First Affiliated Hospital of Chongqing Medical University and Chongqing Key Laboratory of Ophthalmology, Chongqing, China.
Arthritis Rheum. 2012 Dec;64(12):4104-13. doi: 10.1002/art.37708.
To identify susceptibility loci for Behçet's disease (BD) and elucidate their functional role.
A genome-wide association study (GWAS) and functional studies were conducted. A total of 149 patients and 951 controls were enrolled in the initial GWAS, and 554 patients and 1,159 controls were enrolled in the replication study. Real-time polymerase chain reaction, luciferase reporter assay, and enzyme-linked immunosorbent assay were performed.
Our GWAS and replication studies identified a susceptibility locus around STAT4 (single-nucleotide polymorphisms [SNPs] rs7574070, rs7572482, and rs897200; P = 3.36 × 10(-7) to 6.20 × 10(-9) ). Increased expression of STAT4 was observed in individuals carrying the rs897200 risk genotype AA. Consistent with the idea that STAT4 regulates the production of interleukin-17 (IL-17) and interferon-γ, IL17 messenger RNA and protein levels were increased in individuals carrying the rs897200 risk genotype AA. Interestingly, the risk allele A of rs897200 creates a putative transcription factor binding site. To test whether it directly affects STAT4 transcription, an in vitro luciferase reporter gene assay was performed. Higher transcription activity was observed in individuals carrying the risk allele A, suggesting that rs897200 is likely to directly affect STAT4 expression. Additionally, 2 SNPs, rs7574070 and rs7572482, which are tightly linked with rs897200, were cis-expression quantitative trait loci (eQTL) SNPs, suggesting that SNP rs897200 is an eQTL SNP. Most importantly, the clinical disease severity score was higher in individuals with the rs897200 risk genotype AA.
These findings strongly suggest that STAT4 is a novel locus underlying BD. We propose a model in which up-regulation of STAT4 expression and subsequent STAT4-driven production of inflammatory cytokines, such as IL-17, constitute a potential pathway leading to BD.
确定白塞病（BD）的易感基因座并阐明其功能作用。
进行了全基因组关联研究（GWAS）和功能研究。初始GWAS共纳入149例患者和951例对照，重复研究纳入554例患者和1159例对照。进行了实时聚合酶链反应、荧光素酶报告基因检测和酶联免疫吸附测定。
我们的GWAS和重复研究在STAT4周围确定了一个易感基因座（单核苷酸多态性[SNPs]rs7574070、rs7572482和rs897200；P = 3.36×10^(-7)至6.20×10^(-9)）。在携带rs897200风险基因型AA的个体中观察到STAT4表达增加。与STAT4调节白细胞介素-17（IL-17）和干扰素-γ产生的观点一致，携带rs897200风险基因型AA的个体中IL17信使核糖核酸和蛋白质水平升高。有趣的是，rs897200的风险等位基因A创建了一个假定的转录因子结合位点。为了测试它是否直接影响STAT4转录，进行了体外荧光素酶报告基因检测。在携带风险等位基因A的个体中观察到更高的转录活性，表明rs897200可能直接影响STAT4表达。此外，与rs897200紧密连锁的2个SNPs，rs7574070和rs7572482，是顺式表达数量性状基因座（eQTL）SNPs，表明SNP rs897200是一个eQTL SNP。最重要的是，携带rs897200风险基因型AA的个体临床疾病严重程度评分更高。
这些发现强烈表明STAT4是BD的一个新基因座。我们提出了一个模型，其中STAT4表达上调以及随后STAT4驱动的炎性细胞因子如IL-17的产生构成了导致BD的潜在途径。
