Regulatory polymorphisms in the promoter of CXCL10 gene and disease progression in male hepatitis B virus carriers
Regulatory polymorphisms in the promoter of CXCL10 gene and disease progression in male hepatitis B virus carriers
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CXCL10基因启动子调控多态性与男性乙型肝炎病毒携带者疾病进展
DOI：
10.1053/j.gastro.2007.12.044
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发表时间：
2008-03-01
期刊：
影响因子：
29.4
通讯作者：
He, Fuchu
中科院分区：
文献类型：
--
作者：
Deng, Guohong;Zhou, Gangqa;He, Fuchu
背景与目的：10千道尔干扰素γ诱导蛋白（IP-10, CXCL10）在慢性乙型肝炎病毒（HBV）感染中的表达的重要性近年来得到强调。在本报告中，我们研究了CXCL10基因自然发生的序列变异是否影响慢性HBV感染的肝损伤和疾病进展。方法：采用以医院为基础的病例对照研究，分别从北京和重庆招募613例和1787例无血缘关系的汉族乙肝病毒携带者。我们系统地筛选了CXCL10基因的序列变异，并检测了该基因变异与中国北京和重庆人群慢性HBV感染疾病进展易感性之间的关系。进行功能分析以验证相关遗传变异的生物学意义。结果：我们发现位于CXCL10启动子区域的G-201A多态性与男性HBV携带者疾病进展的易感性相关（优势模型，优势比为1.53;P = .001）。功能分析表明，G-201A多态性改变核蛋白结合亲和力，调控CXCL10的表达。我们观察到，在干扰素γ刺激的具有疾病易感基因型的外周血单个核细胞中，CXCL10转录较高。酶联免疫吸附试验和免疫组织化学分析显示，进展期HBV携带者血清和肝组织中CXCL10的产生增加。结论：CXCL10基因启动子中新的调控多态性G-210A可能是个体对慢性HBV感染疾病进展易感性的遗传变异的一部分。
Background & Aims: The importance of expression of interferon gamma-inducible protein of 10 kilodaltons (IP-10, CXCL10) during chronic hepatitis B virus (HBV) infection has been recently emphasized. In this report, we investigated whether the naturally occurred sequence variations in the CXCL10 gene impact liver damage and disease progression of chronic HBV infection. Methods: A hospital-based case-control study was conducted, and a total of 613 and 1787 unrelated Han Chinese HBV carriers were recruited from Beijing and Chongqing, respectively. We systematically screened sequence variations in the CXCL10 gene and examined the association between the variations in this gene and susceptibility to disease progression of chronic HBV infection in Chinese populations from Beijing and Chongqing. Functional analyses were conducted to verify the biological significances of the associated genetic variation. Results: We identified that the polymorphism G-201A, located in the promoter region of CXCL10, was associated with susceptibility to disease progression in male HBV carriers (dominant model; odds ratio, 1.53; P = .001). Functional analyses show that the G-201A polymorphism alters the binding affinity of nuclear protein and regulates CXCL10 expression. We observed higher CXCL10 transcription in interferon gamma-stimulated peripheral blood mononuclear cells with the disease-susceptible genotypes. Enzyme-linked immunosorbent assay and inummohistochemical analysis showed augmented CXCL10 production in serum and liver tissues of progressed HBV carriers. Conclusions: The novel regulatory polymorphism G-210A in the promoter of CXCL10 gene could be a part of the genetic variation underlying the susceptibility of individuals to disease progression of chronic HBV infection.