基于TLR-IFN效应通路基因多态性优化慢性乙型肝炎抗病毒治疗适应症

The mechanism resulting in the low rate of serum immunological response of antiviral therapy of chronic hepatitis B is always the hot topic. Host genetic factors are the dominant factor. Optimizing indications of antivirus therapy has important significance to improve the rate of serum immunological response. In view of TLR-IFN pathway is the core of anti HBV innate immunity and acquired immunity, and the fact that TLR-IFN gene polymorphisms associated with many diseases, this study in order to further optimize the antiviral treatment of chronic hepatitis B indications, improve the rate of serum immunological response. Through case-control genetic association study method, and use functional classification gene chip of TLR-IFN pathways, gene expression associated with serum immunological response/no response is screened. As candidate genes, based on the tagSNP strategy, the SNP site associated with serum immunological responses is identified, and genetic markers of predicting serum immunological response over 80% is screened. A combination of multiple factors is proposed to optimize the anti-HBV therapeutic indications. The study is expected to further clarify the mechanism of individual differences of serum immunological responses in chronic hepatitis B patients with antiviral therapy, and to improve the rate of serum immunological response of antiviral treatment, and to provides a new idea of antiviral therapy in immune tolerance state of chronic HBV infection.

慢性乙型肝炎抗病毒治疗低血清免疫学应答率的机制一直是研究者关注的热点问题，宿主遗传因素在其中占主导地位。对抗病毒治疗适应症进行优化对提高疗效具有重要意义。鉴于TLR-IFN通路处于抗HBV天然免疫和获得性免疫通路的核心，以及其基因多态性与多种疾病关联的事实，本研究以进一步优化慢性乙型肝炎抗病毒治疗适应症、提高疗效为切入点，通过病例-对照遗传关联研究的方法，利用TLR-IFN效应通路功能分类基因芯片筛选出与血清免疫学应答/无应答关联的表达差异基因，并以此为候选基因，再基于tagSNP策略鉴定出与血清免疫学应答关联的SNP位点，筛选出能预测血清免疫学应答80%以上的遗传标记，并结合多种因素提出优化的抗HBV治疗适应症。研究可望进一步明确慢性乙型肝炎患者抗病毒治疗血清免疫学应答个体差异的机制，提高抗病毒治疗血清免疫学应答率，并为处于免疫耐受状态的慢性HBV感染者的抗病毒治疗提供新的思路。

本课题在深入临床研究的基础上，通过蛋白质芯片技术较为全面的对慢性HBV感染不同临床表型的免疫因子表达模式进行了评估，获得了一些有利于HBV清除的免疫特征，明确了细胞因子与炎症活动程度的关联；并通过病例-对照遗传关联研究筛选出了与持续HBV感染、HBeAg阴性慢性乙型肝炎、非活动性HBV携带、HBeAg血清转换等存在关联的基因多态性位点；研究丰富了慢性HBV感染临床表型多样性形成的机制，所筛选出来的免疫特征和基因多态性位点可用于慢性HBV感染的预后评估；相关临床验证和随访正在进行。本课题获得中华医学科技奖三等奖，发表SCI论文5篇。培养博士后研究生1名，博士研究生1名，硕士研究生4名。