title: The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhao
authors.forename: Qibin
authors.initials: Q
authors.lastname: Li
authors.forename: Miaoxin
authors.initials: M
authors.lastname: Li
authors.forename: Caixia
authors.initials: C
authors.lastname: Li
authors.forename: Tingting
authors.initials: T
authors.lastname: Xu
authors.forename: Xiangyi
authors.initials: X
authors.lastname: Jing
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhu
authors.forename: Ye
authors.initials: Y
authors.lastname: Wang
authors.forename: Fucheng
authors.initials: F
authors.lastname: Li
authors.forename: Ruihong
authors.initials: R
authors.lastname: Liu
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhong
authors.forename: Qihao
authors.initials: Q
authors.lastname: Pan
authors.forename: Binghui
authors.initials: B
authors.lastname: Zeng
authors.forename: Qijun
authors.initials: Q
authors.lastname: Liao
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Zhao-xia
authors.initials: ZX
authors.lastname: Hu
authors.forename: Yang-su
authors.initials: YS
authors.lastname: Huang
authors.forename: Pak
authors.initials: P
authors.lastname: Sham
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Shuhua
authors.initials: S
authors.lastname: Xu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Zhi-liang
authors.initials: ZL
authors.lastname: Gao
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D005260:Female; D056726:Genetic Association Studies; D019694:Hepatitis B, Chronic / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics*; D027981:Symporters / Q000235:genetics*
chemical_list: D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter