性激素/性激素受体信号通路基因多态性在慢性HBV感染性别间的差异及其与HBV受体NTCP表达的关系

Males more easily suffered from chronic HBV infection and the concurrency rate of cirrhosis and primary hepatocellular carcinoma in male was higher than in female After infected with HBV,.The clinical outcome of sex disparity in chronic HBV infection has been recognized. At first, researchers focused on the effect of sex hormones. However exogenous hormones or hormone antagonist had not been found affected the progression of disease by animal experiment and the sex disparity of HBV infection was regard as sex hormones combined with sex hormone receptors activating the following signal pathway. But, papers published so far usually are cross sectional study with single liver biopsy of HCV infection and have not clinical data which is subject to a strong potential for reverse causation bias ,although the study analyzed the sex hormone pathway genetic polymorphism. Morever, study about the association between sex hormone pathway genetic polymorphism and sex disparity in chronic HBV infection has been not published. To further discuss the clinical outcome of sex disparity in chronic HBV infection, our group ,which had focused on the mechanism of sex disparity in chronic liver disease and antiviral therapy in chronic HBV/HCV infection, recruites patients following 3years in our register research after participating in the epidemiology registration study of chronic virus liver disease operated in 2010, and analyzes sex hormone/sex hormone receptor signaling pathway gene polymorphism of AKR1C3、AKR1C2、HSD17B6、ESR1 and SRD5A1. Then based on analyzing the expression of HBV receptor NTCP with different sex and different liver disease degree, our team will further discuss sex hormone/sex hormone receptor signaling pathway genetic polymorphism of AKR1C3、AKR1C2、HSD17B6、ESR1 and SRD5A1 and sex disparity. Hopefully new discovery and new proof to sex disparity in chronic HBV infection would be supplied by this study.

针对男性HBV感染慢性化几率明显高于女性的现象，课题组在多年从事慢性肝病性别间差异机制和抗病毒治疗慢性病毒性肝炎影响因素研究的基础上，对曾于2010参加了本学科临床注册研究，并在本学科接受定期随访长达3年以上的患者进行性激素/性激素受体信号通路基因AKR1C3、AKR1C2、HSD17B6、ESR1和SRD5A1单核苷酸多态性分析。评价其在慢性HBV感染性别间的差异以及与疾病严重程度和抗病毒疗效间的关系。此外，还将在分析不同性别及不同临床表型慢性HBV感染者肝组织HBV受体NTCP表达特性的基础上，进一步探讨其在慢性HBV感染者性别间是否存在差异及其与性激素/性激素受体通路基因AKR1C3、AKR1C2、HSD17B6、ESR1和SRD5A1多态性的关系。希望能有所突破，能为慢性HBV感染在性别间差异机制的研究提供新的依据。

本研究从观察性激素/性激素受体信号通路上关键调控因子的表达入手，探讨了慢性HBV感染者性别间差异的机制。. 以参加本学科慢性病毒性肝炎流行病学注册研究（注册号：ChiCTR-ECS-13004009）及抗病毒治疗注册研究（注册号：ChiCTR-PRCH-13003986）的患者群为研究对象，先是通过高通量测序，对性激素/性激素受体信号通路调控因子AKR1C2、AKR1C3、HSD17B6、SRD5A1、SED5A2、ESR1 6个基因30个位点单核苷酸多态性进行分析，之后通过分析慢性HBV感染者肝组织中AR以及正反馈通路上重要调控因子CCRK/STAT3的表达，探讨其在性别间的差异以及与疾病进展的关系。最后课题组还探讨了慢性HBV感染者肝组织HBV进入受体NTCP的表达特征及其与疾病进展的关系。.主要研究成果：1、在性激素/性激素受体信号通路上的6个基因30个位点上发现SDR5A2基因rs12470143和rs7594951位点及ESR1基因rs223469位点的单核苷酸多态性在性别间存在差异，并与临床特征及疾病进展程度相关； 2、发现AR以及AR/CCRK/STAT3正反馈信号通路上3个因子在慢性HBV感染者肝组织的表达明显高于非HBV感染者，而且与肝组织HBV DNA载量、疾病进展程度相关，并在性别间存在差异；3、发现慢性HBV感染者肝组织HBV进入受体在肝组织的表达与HBV DNA载量、METAVIR炎症评分和纤维化评分相关。虽然慢性HBV感染者肝组织NTCP平均表达水平在性别间并无差异，但若将患者进一步分层，则发现年龄≤55岁女性者肝组织NTCP的表达低于年龄＞55岁者，而且也明显低于同龄且纤维化程度相同的男性慢性HBV感染者。. 综上结果提示性激素/性激素受体信号通路上的关键调控因子及HBV进入受体NTCP的活性是慢性HBV感染性别间差异的重要因素。