Department of Infectious Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory of Liver Diseases, Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Hepatology. 2015 Apr;61(4):1251-60. doi: 10.1002/hep.27608. Epub 2015 Feb 23.
In the past 50 years there have been considerable efforts to identify the cellular receptor of hepatitis B virus (HBV). Recently, in vitro evidence from several groups has shown that the sodium-taurocholate cotransporting polypeptide (NTCP, which is encoded by SLC10A1 and transports bile acids into hepatic cells in enterohepatic recirculation) is a strong candidate. In particular, in vitro the p.Ser267Phe variation of SLC10A1 results in loss of HBV receptor function. We tested the role of NTCP as a receptor for HBV in chronic hepatitis B patients using a genetic association study. We selected SLC10A1 variants from 189 exomes. We used Sanger sequencing to follow up the association of the various SLC10A1 variants in a Han Chinese cohort of 1899 chronic hepatitis B patients and 1828 healthy controls. We further investigated the potential impact of the p.Ser267Phe variant on NTCP function using structural analysis. The p.Ser267Phe variant was associated with healthy status (P = 5.7 × 10(-23) , odds ratio = 0.36) irrespective of hepatitis B virus surface antibody status (P = 6.2 × 10(-21) and 1.5 × 10(-10) , respectively, when the cases were compared with hepatitis B virus surface antibody-positive and -negative controls). The variation was also associated with a lower incidence of acute-on-chronic liver failure (P = 0.007). The estimated heritability explained by this single variation was ∼3.2%. The population prevented fraction was around 13.0% among the southern Chinese. Our structural modeling showed that the p.Ser267Phe variant might interfere with ligand binding, thereby preventing HBV from cellular entry.
The p.Ser267Phe NTCP variant is significantly associated with resistance to chronic hepatitis B and a lower incidence of acute-on-chronic liver failure. Our results support that NTCP is a cellular receptor for HBV in human infection.
在过去的 50 年中，人们做出了大量努力来鉴定乙型肝炎病毒 (HBV) 的细胞受体。最近，几个研究小组的体外证据表明，牛磺胆酸钠共转运多肽 (NTCP，由 SLC10A1 编码，在肠肝循环中胆汁酸转运到肝细胞内) 是一个强有力的候选者。特别是，体外 SLC10A1 的 p.Ser267Phe 变异导致 HBV 受体功能丧失。我们使用遗传关联研究来测试 NTCP 作为慢性乙型肝炎患者 HBV 受体的作用。我们从 189 个外显子中选择了 SLC10A1 变体。我们使用 Sanger 测序来跟进各种 SLC10A1 变体在 1899 名慢性乙型肝炎患者和 1828 名健康对照者的汉族队列中的关联。我们进一步使用结构分析研究了 p.Ser267Phe 变体对 NTCP 功能的潜在影响。p.Ser267Phe 变体与健康状态相关（P=5.7×10(-23) ，比值比=0.36），而与乙型肝炎病毒表面抗体状态无关（当病例与乙型肝炎病毒表面抗体阳性和阴性对照进行比较时，P=6.2×10(-21) 和 1.5×10(-10) ）。该变体还与慢性乙型肝炎急性肝衰竭的发生率较低相关（P=0.007）。该单一变异解释的遗传率约为 3.2%。在中国南方人群中，该变异的人群预防率约为 13.0%。我们的结构建模表明，p.Ser267Phe 变异可能干扰配体结合，从而阻止 HBV 进入细胞。
p.Ser267Phe NTCP 变体与慢性乙型肝炎的耐药性和慢性乙型肝炎急性肝衰竭的发生率较低显著相关。我们的结果支持 NTCP 是人类感染 HBV 的细胞受体。
