Sodium taurocholate co-transporting polypeptide (NTCP) is a cell receptor for HBV. The S267F variant on the NTCP gene is inversely associated with the chronicity of HBV infection, progression to cirrhosis and hepatocellular carcinoma in East Asian populations. The aim of this study was to determine whether the S267F variant was associated with response to pegylated interferon (PEG-IFN) in patients with chronic HBV infection.
Methods
A total of 257 patients with chronic HBV, treated with PEG-IFN for 48 weeks, were identified from 13 tertiary hospitals included in the hepatitis B database of the Thai Association for the Study of the Liver (THASL).
Results
Of these, 202 patients were infected with HBV genotype C (84.9%); 146 patients were hepatitis B e antigen (HBeAg)-positive (56.8%). Genotypic frequencies of the S267F polymorphism were 85.2%, 14.8% and 0% for the GG, GA and AA genotypes, respectively. S267F GA was associated with sustained alanine aminotransferase (ALT) normalization (OR = 3.25, 95% CI 1.23, 8.61; P=0.02) in HBeAg-positive patients. Patients with S267F variant tended to have more virological response, sustained response with hepatitis B surface antigen (HBsAg) loss at 24 weeks following PEG-IFN treatment. There was no association between the S267F variant and improved patient outcomes in HBeAg-negative patients.
Conclusions
The S267F variant on the NTCP gene is independently associated with sustained normalization of ALT following treatment with PEG-IFN in patients with HBV infection who are HBeAg-positive. The findings of this study provide additional support for the clinical significance of the S267F variant of NTCP beyond HBV entry.
References
1.
LiawY.F., ChuC.M.Hepatitis B virus infection.Lancet2009; 373: 582–592.
2.
JanssenH.L., van ZonneveldM., SenturkH.Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.Lancet2005; 365: 123–129.
3.
RijckborstV., ter BorgM.J., CakalogluY.A randomized trial of peginterferon alpha-2a with or without ribavirin for HBeAg-negative chronic hepatitis B.Am J Gastroenterol2010; 105: 1762–1769.
4.
LauD.T., EverhartJ., KleinerD.E.Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa.Gastroenterology1997; 113: 1660–1667.
5.
LinS.M., SheenI.S., ChienR.N., ChuC.M., LiawY.F.Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.Hepatology1999; 29: 971–975.
6.
NiederauC., HeintgesT., LangeS.Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.N Engl J Med1996; 334: 1422–1427.
7.
LauG.K., PiratvisuthT., LuoK.X.Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.N Engl J Med2005; 352: 2682–2695.
8.
YanH., ZhongG., XuG.Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus.eLife2012; 1: e00049.
9.
Kullak-UblickG.A., StiegerB., MeierP.J.Enterohepatic bile salt transporters in normal physiology and liver disease.Gastroenterology2004; 126: 322–342.
10.
StiegerB.The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation.Handb Exp Pharmacol2011; 201: 205–259.
11.
NiY., LemppF.A., MehrleS.Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes.Gastroenterology2014; 146: 1070–1083.
12.
Okuyama-DobashiK., KasaiH., TanakaT.Hepatitis B virus efficiently infects non-adherent hepatoma cells via human sodium taurocholate cotransporting polypeptide.Sci Rep2015; 5: 17047.
13.
IwamotoM., WatashiK., TsukudaS.Evaluation and identification of hepatitis B virus entry inhibitors using HepG2 cells overexpressing a membrane transporter NTCP.Biochem Biophys Res Commun2014; 443: 808–813.
14.
WatashiK., SluderA., DaitoT.Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP).Hepatology2014; 59: 1726–1737.
15.
PetersenJ., DandriM., MierW.Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein.Nat Biotechnol2008; 26: 335–341.
16.
VolzT., AllweissL., BenM.M.The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus.J Hepatol2013; 58: 861–867.
17.
NkongoloS., NiY., LemppF.A.Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor.J Hepatol2014; 60: 723–731.
18.
YanH., PengB., LiuY.Viral entry of hepatitis B and D viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide.J Virol2014; 88: 3273–3284.
19.
HoR.H., LeakeB.F., RobertsR.L., LeeW., KimR.B.Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition.J Biol Chem2004; 279: 7213–7222.
20.
PengL., ZhaoQ., LiQ.The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B.Hepatology2015; 61: 1251–1260.
21.
LiN., ZhangP., YangC.Association of genetic variation of sodium taurocholate cotransporting polypeptide with chronic hepatitis B virus infection.Genet Test Mol Biomarkers2014; 18: 425–429.
22.
HuH.H., LiuJ., LinY.L.The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B.Gut2016; 65: 1514–1521.
European Association For The Study Of The Liver.EASL clinical practice guidelines: management of chronic hepatitis B virus infection.J Hepatol2012; 57: 167–185.
25.
LiawY.F., KaoJ.H., PiratvisuthT.Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update.Hepatol Int2012; 6: 531–561.
26.
MiccoL., PeppaD., LoggiE.Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B.J Hepatol2013; 58: 225–233.
27.
HaoJ., JinW., LiX.Inhibition of alpha interferon (IFN-alpha)-induced microRNA-122 negatively affects the anti-hepatitis B virus efficiency of IFN-alpha.J Virol2013; 87: 137–147.
28.
SonneveldM.J., WongV.W., WoltmanA.M.Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B.Gastroenterology2012; 142: 513–520.e511.
29.
JiangD.K., WuX., QianJ.Genetic variation in STAT4 predicts response to interferon-alpha therapy for hepatitis B e antigen-positive chronic hepatitis B.Hepatology2016; 63: 1102–1111.
30.
LamperticoP., ViganoM., CheroniC.IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B.Hepatology2013; 57: 890–896.
31.
ZhangQ., LapalusM., AsselahT.IFNL3 (IL28B) polymorphism does not predict long-term response to interferon therapy in HBeAg-positive chronic hepatitis B patients.J Viral Hepat2014; 21: 525–532.
32.
LimothaiU., WasitthankasemR., PoovorawanY., TangkijvanichP.Single nucleotide polymorphism of interferon lambda-4 gene is not associated with treatment response to pegylated interferon in Thai patients with chronic hepatitis B.Asian Pac J Cancer Prev2015; 16: 5515–5519.
33.
de NietA., TakkenbergR.B., BenayedR.Genetic variation in IL28B and treatment outcome in HBeAg-positive and -negative chronic hepatitis B patients treated with peg interferon alfa-2a and adefovir.Scand J Gastroenterol2012; 47: 475–481.
34.
GalmozziE., ViganoM., LamperticoP.Systematic review with meta-analysis: do interferon lambda 3 polymorphisms predict the outcome of interferon-therapy in hepatitis B infection?Aliment Pharmacol Ther2014; 39: 569–578.
35.
TsengT.C., YuM.L., LiuC.J.Effect of host and viral factors on hepatitis B e antigen-positive chronic hepatitis B patients receiving pegylated interferon-alpha-2a therapy.Antivir Ther2011; 16: 629–637.
36.
BrouwerW.P., SonneveldM.J., TabakF.Polymorphisms of HLA-DP are associated with response to peginterferon in Caucasian patients with chronic hepatitis B.Aliment Pharmacol Ther2014; 40: 811–818.
37.
PanW., SongI.S., ShinH.J.Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations.Xenobiotica2011; 41: 501–510.
38.
YangJ., YangY., XiaM.A genetic variant of the NTCP gene is associated with HBV infection status in a Chinese population.BMC Cancer2016; 16: 211.
39.
SuZ., LiY., LiaoY.Polymorphisms in sodium taurocholate cotransporting polypeptide are not associated with hepatitis B virus clearance in Chinese Tibetans and Uygurs.Infect Genet Evol2016; 41: 128–134.
40.
KonigA., DoringB., MohrC., GeipelA., GeyerJ., GlebeD.Kinetics of the bile acid transporter and hepatitis B virus receptor Na+/taurocholate cotransporting polypeptide (NTCP) in hepatocytes.J Hepatol2014; 61: 867–875.
41.
TangkijvanichP., KomolmitP., MahachaiV., Sa-nguanmooP., TheamboonlersA., PoovorawanY.Low pretreatment serum HBsAg level and viral mutations as predictors of response to PEG-interferon alpha-2b therapy in chronic hepatitis B.J Clin Virol2009; 46: 117–123.
