Diverse Effects of the NTCP p.Ser267Phe Variant on Disease Progression During Chronic HBV Infection and on HBV preS1 Variability.

Fangji Yang,Tongtong Chen,Lina Wu,Qian Jiao,Limin Zhen,Liang Peng,Wenxiong Xu,Yongyuan Zheng,Ying Liu,Jie Song,Gang Ning,Chan Xie

doi:10.3389/fcimb.2019.00018

Abstract

The sodium taurocholate co-transporting polypeptide (NTCP) acts as a cellular receptor for the hepatitis B virus (HBV) infection on host hepatocytes. We aim to investigate how the NTCP p.Ser267Phe variant affects HBV-related disease progression and analyze viral genomic variability under a host genetic background carrying the p.Ser267Phe variant. A total of 3187 chronic hepatitis B (CHB) patients were enrolled and genotyped for the p.Ser267Phe variant. The variant's association with disease progression was evaluated by logistic regression analysis. We also enrolled 83 treatment-naive CHB patients to analyze the variability of the HBV preS1 region. The frequency of the NTCP p.Ser267Phe variant was significantly lower in patients diagnosed with acute-on-chronic liver failure [OR (95% CI) = 0.33 (0.18–0.58), P = 1.34 × 10−4], cirrhosis [OR (95% CI) = 0.47 (0.31–0.72), P = 4.04 × 10−4], and hepatocellular carcinoma [OR (95% CI) = 0.54 (0.34–0.86), P = 9.83 × 10−3] as compared with CHB controls under the additive model after adjustment. Furthermore, the percentage of amino acid mutations in HBV preS1 region was significantly higher in the NTCP p.Ser267Phe heterozygote group than in the NTCP wild type homozygote group (P < 0.05). We herein demonstrate that the NTCP p.Ser267Phe variant is a protective factor reducing CHB patient risk for liver failure, cirrhosis, and hepatocellular carcinoma. A host genetic background carrying NTCP p.Ser267Phe exerts selective pressure on the virus, leading to more variability.

Highlights

Hepatitis B virus (HBV) infection constitutes a public health challenge, which affects more than 250 million people worldwide (Trepo et al, 2014)
Mean age of each group increased in the order of chronic hepatitis B (CHB) (35.56 ± 10), acute-on-chronic liver failure (ACLF) (41.61 ± 10), Cirrhosis (CIR) (46.67 ± 10), and hepatocellular carcinoma (HCC) (47.82 ± 10)
We found that the minor allele (A) plays a protective effect in CHB patients, conferring an approximately 70% reduction in risk for developing liver failure (Table 2), a 50% reduction in risk for developing cirrhosis (Table 3), and a 40% reduction in risk for developing HCC (Table 4)

Summary

Introduction

Hepatitis B virus (HBV) infection constitutes a public health challenge, which affects more than 250 million people worldwide (Trepo et al, 2014). Varying clinical outcomes of HBV infection are affected by a complex combination of virus and host factors, NTCP p.Ser267Phe Variant and HBV such as viral genomic variability, host immunological state, and host genetic background (Hu et al, 2013; Al-Qahtani et al, 2018; Tan et al, 2018b). The HBV virus comprises an external envelope composed of surface glycoproteins, an icosahedral nucleocapsid, and a 3.2 kb partially double-stranded DNA genome. It was discovered that HBV entry into human hepatocytes is mediated by the receptor sodium taurocholate co-transporting polypeptide (NTCP) expressed by the host (Yan et al, 2012; Ni et al, 2014). The preS1 domain of large envelope proteins is responsible for its binding with NTCP and involved in virus–host receptor interaction (Barrera et al, 2005; Glebe et al, 2005; Yan et al, 2012)

Objectives

Results

Conclusion