中国汉族人群中TLR7基因拷贝数变异与眼部白塞病的关联
Association Between Copy Number Variations of TLR7 and Ocular Behçet's Disease in a Chinese Han Population.
作者信息
Fang Jing, Chen Lu, Tang Jihong, Hou Shengping, Liao Dan, Ye Zi, Wang Chaokui, Cao Qinfeng, Kijlstra Aize, Yang Peizeng
机构信息
The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China Department of Ophthalmology, Children's Hospital, Chongqing Medical University, Chongqing, China.
The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, China.
出版信息
Invest Ophthalmol Vis Sci. 2015 Feb 3;56(3):1517-23. doi: 10.1167/iovs.14-15030.
PURPOSE
The purpose of this study was to test whether gene copy number variations (CNVs) of Toll-like receptors (TLRs) are associated with uveitis.
METHODS
Copy number variations of TLRs were detected by real-time PCR. The first stage of the study consisted of enrolling 400 Behçet's disease (BD) patients, 400 Vogt-Koyanagi-Harada syndrome patients, 400 patients with acute anterior uveitis associated with or without ankylosing spondylitis, and 600 healthy subjects. The second stage included another set of 578 BD patients and 1000 healthy controls. The frequencies of TLR gene copy number types (TLR1, TLR2, TLR3, TLR5, TLR6, TLR7, TLR9, TLR10) were compared among patients and controls by using the χ(2) test. Real-time PCR was used to detect mRNA expression from peripheral blood mononuclear cells (PBMCs) obtained from healthy controls following stimulation with the TLR7 agonist R848. Levels of TNF-α, IL-6, IL-1β, and IFN-β in culture supernatants were measured by ELISA.
RESULTS
All TLRs tested, except for TLR7, had a gene copy number of two in more than 98% of individuals tested. In the first stage, we found a significantly increased frequency of more than one copy of TLR7 (located on the X chromosome) in male BD patients and more than two copies in female patients (correction of P value [PC] = 0.021; PC = 0.048, respectively). A second stage and combined study confirmed the association (PC = 1.14 × 10(-6); PC = 9.12 × 10(-5), respectively). TLR7 mRNA expression in PBMCs was increased in healthy male carriers having more than one copy of TLR7 or females having more than two copies following stimulation with R848 (P = 0.021, P = 0.006, respectively). No effect of the various TLR7 copies on the release of TNF-α, IL-6, IL-1β, and IFN-β could be detected.
CONCLUSIONS
This study provides evidence that a high copy number of TLR7 confers risk for BD in a Chinese Han population. (http://www.chictr.org number, ChiCTR-CCC-12002184.).
目的
本研究旨在检测Toll样受体（TLR）的基因拷贝数变异（CNV）是否与葡萄膜炎相关。
方法
采用实时PCR检测TLR的拷贝数变异。研究的第一阶段纳入400例白塞病（BD）患者、400例Vogt-小柳原田综合征患者、400例伴或不伴强直性脊柱炎的急性前葡萄膜炎患者以及600名健康受试者。第二阶段纳入另外一组578例BD患者和1000名健康对照。采用χ²检验比较患者和对照中TLR基因拷贝数类型（TLR1、TLR2、TLR3、TLR5、TLR6、TLR7、TLR9、TLR10）的频率。采用实时PCR检测健康对照外周血单个核细胞（PBMC）经TLR7激动剂R848刺激后的mRNA表达。采用ELISA检测培养上清中TNF-α、IL-6、IL-1β和IFN-β的水平。
结果
除TLR7外，所有检测的TLR在超过98%的受检个体中基因拷贝数为两个。在第一阶段，我们发现男性BD患者中TLR7（位于X染色体）拷贝数多于一个的频率显著增加，女性患者中多于两个拷贝的频率显著增加（校正P值[PC]分别为0.021；PC = 0.048）。第二阶段及联合研究证实了这种关联（PC分别为1.14×10⁻⁶；PC = 9.12×10⁻⁵）。R848刺激后，TLR7拷贝数多于一个的健康男性携带者或多于两个拷贝的女性携带者的PBMC中TLR7 mRNA表达增加（P分别为0.021，P = 0.006）。未检测到不同TLR7拷贝数对TNF-α、IL-6、IL-1β和IFN-β释放的影响。
结论
本研究提供了证据表明TLR7高拷贝数在中国汉族人群中赋予BD患病风险。（http://www.chictr.org编号，ChiCTR-CCC-12002184。）
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