The p.Ser267Phe Variant in SLC10A1 Is Associated With Resistance to Chronic Hepatitis B
The p.Ser267Phe Variant in SLC10A1 Is Associated With Resistance to Chronic Hepatitis B
复制标题
SLC10A1 中的 p.Ser267Phe 变体与慢性乙型肝炎抵抗力相关
DOI：
10.1002/hep.27608
复制
发表时间：
2015-04-01
期刊：
影响因子：
13.5
通讯作者：
Wang, Yiming
中科院分区：
文献类型：
--
作者：
Peng, Liang;Zhao, Qiang;Wang, Yiming
在过去的50年里，人们已经做出了相当大的努力来鉴定B型肝炎病毒（HBV）的细胞受体。最近，来自几个小组的体外证据表明，钠-牛磺胆酸盐共转运多肽（NTCP，由SLC 10A 1编码，在肝肠再循环中将胆汁酸转运到肝细胞中）是一个强有力的候选者。特别地，在体外，SLC 10A 1的p.Ser267Phe变异导致HBV受体功能的丧失。我们使用遗传关联研究来检测NTCP作为HBV受体在慢性B型肝炎患者中的作用。我们从189个外显子组中选择了SLC 10A 1变体。我们使用桑格测序法对1899例慢性B型肝炎患者和1828例健康对照者的中国汉族队列中各种SLC 10 A1变异的相关性进行了随访。我们使用结构分析进一步研究了p.Ser267Phe变体对NTCP功能的潜在影响。p.Ser267Phe变异体与健康状态相关（P=5.7 × 10（，）（-23）比值比=0.36），与B型肝炎病毒表面抗体状态无关（当病例与B型肝炎病毒表面抗体阳性和阴性对照相比时，P分别为6.2 × 10（-21）和1.5 × 10（-10））。这种变化也与慢性加急性肝衰竭的发生率较低相关（P=0.007）。由这一单一变异解释的遗传力估计值约为3.2%。南方人群预防率为13.0%左右。我们的结构模型显示p.Ser267Phe变异体可能干扰配体结合，从而阻止HBV进入细胞。结论：p.Ser267Phe NTCP变异体与慢性B型肝炎的抵抗力和慢性加急性肝衰竭的发生率较低显著相关。我们的研究结果支持NTCP是HBV在人类感染中的细胞受体。（肝病学2015;61：1251-1260）
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 x 10(,)(-23) odds ratio=0.36) irrespective of hepatitis B virus surface antibody status (P=6.2 x 10(-21) and 1.5 x 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 approximate to 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. Conclusion: 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. (Hepatology 2015;61:1251-1260)