NTCP基因编码区非同义突变对HBV易感性的影响及机制研究

As a functional receptor for hepatitis B virus, Na+-Taurochaolate Cotransporting Polypeptide (NTCP) plays an important role to initiate the process of hepatitis B virus (HBV) infection, however, the expression pattern (expression amount and cellular localization) of NTCP in liver cells exhibits significant individual differences. Recent studies have shown that the non-synonymous mutations in coding region of NTCP gene were associated with bile acid substrate recognition and may affect the ability to transport bile acid. In our prevous case-control study with a small sample, we also found a obvious trend that the non-synonymous mutations in coding region of NTCP may be associated with HBV infection of babies born in pregnant women infected high load HBV. Futhermore, the data from bioinformatics also supported our viewpiont that some non-synonymous mutations in coding region of NTCP may change the structure and function of the NTCP. Then, in this project, we plan to perform a genetic case-control study (cases from the patients which infected HBV from the mother-to-child transmission, controls from the HBV-uninfected babies born in pregnant women infected high load HBV) to indentify the non-synonymous mutation(s) associated with susceptibility to HBV infection. To verify the function reveal the mechanism of the the aasocated the non-synonymous mutation(s), we also plan to perform a serial fuctional study. The expected results of our study may not only emphasize the inportance of NTCP in the pathophsiology of HBV infection on the population level, provide the clinicians new ideas to personalized prevention strategies of HBV infection, but also provide the researchers new clues to further research such as drug development.

钠离子/牛磺胆酸共转运多肽(NTCP)是HBV功能性受体，在HBV感染过程中起到重要始动作用，但其在细胞中的浆膜分布及细胞表面的表达存在显著个体差异。既往研究表明NTCP编码区变异可影响肝细胞的胆酸转运能力；我们初步研究提示NTCP突变可能与HBV感染孕妇所生婴儿是否感染HBV相关；生物信息学预测NTCP非同义突变会改变NTCP蛋白的结构和功能，进而在启动HBV感染机制中发挥关键作用。本研究拟以HBV感染孕妇所生子代为研究对象，采用基于病例(母婴传播患者)-对照(HBV孕妇所生未感染HBV者)的遗传关联研究，从群体水平证实NTCP基因突变对HBV易感性的影响。同时构建不同NTCP变异体，在细胞水平验证NTCP突变对HBV感染的影响，分析NTCP突变对肝细胞中NTCP浆膜分布和细胞表面表达的影响，以期深入认识NTCP变异在HBV感染机制中的作用，为HBV感染预警和后期药物开发提供分子靶标。

钠离子/牛磺胆酸共转运多肽(NTCP)是 HBV功能性受体，在 HBV感染过程中起到重要始动作用，但其在细胞中的浆膜分布及细胞表面的表达存在显著个体差异。既往研究表明NTCP编码区变异可影响肝细胞的胆酸转运能力；生物信息学预测 NTCP非同义突变会改变 NTCP蛋白的结构和功能，进而在启动 HBV感染机制中发挥关键作用。本研究以 HBV感染孕妇所生子代为研究对象，采用基于病例(母婴传播患者)-对照(HBV孕妇所生未感染 HBV者)的遗传关联研究，从群体水平证实 NTCP基因突变对 HBV易感性的影响,rs36115704（c.356+1098C＞T）、rs10459536（c.5683169A＞C）以及rs7154439（c.-1956G＞A）位点变异与人群对HBV母婴传播易感性相关。同时构建不同 NTCP变异体，在细胞水平验证 NTCP突变对 HBV感染的影响，分析 NTCP突变对肝细胞中 NTCP浆膜分布和细胞表面表达的影响。