机体自发清除HCV和HLA遗传多态性的关联研究

Approximately 15%-40% of hepatitis C virus (HCV) infected individuals are capable of clearing the virus spontaneously, while the majority progress into chronic infection. Genetic diversity on human leukocyte antigen (HLA) is believed to contribute to the spontaneous clearance of HCV. Recently we have performed HLA high-resolution genotyping on 426 HCV RNA positive and 709 healthy individuals, which revealed the association of one HLA-A genotype and five HLA-DRB1 alleles with HCV susceptibility. These results implied that HLA is an affecting or even a determinant factor of the infection or its clearance. In this proposal we will set up a case-control study on 2100 HCV-infected individuals who are recruited from volunteer blood donors in Guangdong province (All will be or have been followed up at an interval of ≥ 6 months). These individuals will be divided into two groups, the spontaneous clearance group and the chronic infection group, according to the results of nucleic acid amplification test (NAT) for HCV RNA. We will use the PCR-SSO method and luminex fluorescent-bead assay to complete high-resolution HLA genotyping. The results will be statistically analyzed to demonstrate the association of HLA genetic diversity with HCV spontaneous clearance. Scientific evidence will be provided for the development of HCV vaccine and individualized treatment.

人体感染HCV后，有15%-40%的个体能在6个月之内自发清除病毒，其余转为慢性感染。机体自发清除HCV可能和感染者的HLA复合物的遗传多态性有关。我们前期的研究中对426例HCV RNA阳性的慢性感染者和709例健康献血者进行HLA高分辨分型，发现HLA-A位点1个基因型和HLA-DRB1位点5个等位基因与HCV感染存在显著关联，提示HLA很可能参与甚至决定了机体感染或清除HCV的过程。本项目拟采用病例对照的研究方法，对广东地区无偿献血人群中2100名HCV感染者进行随访（至少6个月），根据HCV RNA检测结果将其分为自发清除HCV组和慢性感染组，采用PCR-SSO流式荧光磁珠法对2组研究对象进行HLA高分辨分型，通过统计学关联分析揭示HLA 多态性与机体自发清除HCV的关联性，从而为HCV疫苗的研制和个体化治疗方案的制定提供科学依据。

丙型肝炎是一种严重危害人类健康的常见病和多发病，由丙型肝炎病毒（Hepatitis C Virus，HCV）引起，主要经血源传播。人体感染HCV后，有15%-40%的个体能在6个月之内自发清除病毒，其余转为慢性感染。本项目通过对抗-HCV抗体阳性的无偿献血者和吸毒人群进行HCV RNA 检测，然后每半年随访1次，每次随访时抽取外周血做抗-HCV、HCV RNA检测。将随访2次以上仍然保持HCV RNA阴性、又未经任何治疗的人员归为自发清除病毒组，将一直保持HCV RNA阳性的列为慢性HCV感染组。我们发现在HCV感染的献血人群中，男性的HCV清除率为13.43%（162/1026），低于女性献血者的31.88%（102/320）（P<0.01）;同样在HCV感染的吸毒人群中，男性的HCV清除率为11.30% (60/531),低于女性的21.77%(64/294) （P<0.01）；同时发现在HBV/HCV共感染的献血人群和吸毒人群，其自发清除HCV的比例分别达39.47%（15/38）和41.38%(60/145)，明显高于单独感染HCV人群的16.73%和9.41%。另外我们也发现IL28B rs8099917的 TT基因型有利于HCV的清除。Logistic回归和多因素分析发现感染者的性别、是否合并HBV感染、IL28B基因型是影响机体自发清除HCV的因素，且献血人群较吸毒人群更易清除HCV。对231名自发清除HCV和429名慢性HCV感染的献血者进行HLA-A, B, C, DPB1, DQB1 和DRB1高分辨分型，发现HLA-A*02:01是与机体自发清除HCV相关联的HLA-Ⅰ类基因[Odds ratio (OR) =1.839, p=0.004, pc（为经Bonferroni 校正后的p值）=0.024]，HLA-DRB1*11:01是与机体自发清除HCV相关联的HLA-Ⅱ类基因（OR= 1.921,P= 0.005）。我们的研究结果将为HCV疫苗的研制和个体化治疗方案的制定提供帮助。

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