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.Ser267-Phe variant on NTCP function using structural analysis. The p.Ser267Phe variant was associated with healthy status (P 5 5.7 3 10 223 , odds ratio 5 0.36) irrespective of hepatitis B virus surface antibody status (P 5 6.2 3 10 221 and 1.5 3 10 210 , 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 5 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. (HEPATOLOGY 2015;61:1251-1260 C hronic hepatitis B (CHB) affects approximately 240 million people worldwide and is responsible for about 780,000 deaths annually (http://www.who.int/mediacentre/factsheets/fs204/en/).Clinically, CHB holds the most significant medical consequences among hepatitis B virus (HBV)-infected individuals. Acute-on-chronic liver failure (ACLF) is the most urgent and lethal condition related to CHB.Abbreviations: ACLF, acute-on-chronic liver failure; AIM, ancestry-informative marker; ASBT, apical sodium-dependent bile acid transporter; CHB, chronic hepatitis B; HBV, hepatitis B virus; HBsAb, hepatitis B virus surface antibody; HBsAg, hepatitis B virus surface antigen; HDV, hepatitis D virus; NTCP, sodiumtaurocholate cotransporting polypeptide..From the

Unusual Features of Sodium Taurocholate Cotransporting Polypeptide as a Hepatitis B Virus Receptor

“…Conversely, introduction of NTCP cDNA into HepG2 and Huh7 cells conferred susceptibility to infection by HBV and HDV, respectively (16). These seminal findings established NTCP as an HBV and HDV receptor, a demonstration that has been independently confirmed and extended (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Consequently, NTCP substrates or inhibitors such as tauroursodeoxycholic acid (TUDCA), cyclosporine, irbesartan, and ritonavir could suppress ccHBV or HDV infection (18,(20)(21)(22)(23)(24).…”

Lentiviral hepatitis B pseudotype entry requires sodium taurocholate co-transporting polypeptide and additional hepatocyte-specific factors

“…HBVpp entry is NTCP-dependent; however, expression of NTCP in non-liver epithelial cells does not confer permissivity to infection, suggesting that additional hepatocyte-specific factors are required. The recent report of a genetic polymorphism (p.Ser267Phe) in NTCP that ablates HepG2 ability to support HBV infection in vitro and yet supports HBV infection in man (Peng et al, 2015) suggests that additional host factors are required for HBV entry. Taken together, these results highlight the utility of the pseudovirus approach to dissect the molecular pathways of HBV entry into the liver.…”

Letter: factors determining liver fibrosis – more to come

“…The prevalence of the protective allele (T) was much higher than that (8.1%) reported by Peng et al 5 Patients with the heterozygous SLC10A1 genotype were more likely to have insignificant fibrosis at baseline (LSM ≤5.0 kPa) than the homozygotes (89.9% vs. 62.3%, P < 0.001). They tended to have a lower risk of fibrosis progression during follow-up (1.4% vs. 3.7%), though it did not reach statistical significance because of the small number of events (P = 0.352; Table 1).…”

“…4 On the other hand, the role of SLC10A1 variants on the severity and progression of liver fibrosis in CHB patients has not been established in this cross-sectional study. 5 We previously reported a cohort of 361 CHB patients with inactive disease, which was defined as negative hep- Letters to the Editors…”