The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B.

Abstract

UNLABELLED 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. 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.

DOI: 10.1002/hep.27608

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@article{Peng2015ThePV, title={The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B.}, author={Liang Peng and Qiang Zhao and Qibin Li and Miaoxin Li and Caixia Li and Tingting Xu and Xiangyi Jing and Xiang Zhu and Ye Wang and Fucheng Li and Ruihong Liu and Cheng Zhong and Qihao Pan and Binghui Zeng and Qijun Liao and Bin Hu and Zhao-xia Hu and Yang-su Huang and Pak Sham and Jinsong Liu and Shuhua Xu and Jun Wang and Zhi-Liang Gao and Yiming Wang}, journal={Hepatology}, year={2015}, volume={61 4}, pages={1251-60} }