br Introduction Although effective hepatitis B
Introduction Although effective hepatitis B virus (HBV) vaccines are in use worldwide, HBV-related liver diseases are still a major public health concern, causing considerable morbidity and mortality. Approximately 257 million people are currently suffering from chronic hepatitis B and 887,000 deaths have been recorded in 2015 due to HBV infection (WHO, 2017a). HBV causes various clinical conditions, including acute hepatitis B, chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC) (Liaw and Chu, 2009, WHO, 2017a). The risk of HCC development in chronic HBV carriers is approximately 40 times higher than that in non-carriers (Lee et al., 2013). Hepatitis D virus (HDV), an RNA virus first identified in 1977 (Rizzetto et al., 1977), can cause disease only in the presence of preexisting HBV infection, as it requires HBV envelope proteins for effective infection of hepatocytes (Sureau and Negro, 2016). HDV particles contain a circular single-stranded RNA of 1679 nucleotides and two viral proteins, the small and large hepatitis D antigens, which are surrounded by an outer coat containing HBV-derived envelope proteins and host phospholipids (Hughes et al., 2011). HDV coinfection affects 15–20 million HBV carriers worldwide (Noureddin and Gish, 2014, WHO, 2017b). HDV infection is associated with an increased risk of LC and HCC development (Hughes et al., 2011). As both HDV and HBV utilize identical proteins, they may enter the hepatocytes through similar mechanisms. Recently, the sodium taurocholate co-transporting polypeptide (NTCP) receptor has been identified as a cellular receptor for both HBV and HDV entry (Ni et al., 2014, Yan et al., 2012). A homozygous non-synonymous Arg252His substitution in the NTCP was associated with the impaired uptake of bile salts into hepatocytes, confirming the important role of this hepatic bile vomitoxin transporter (Vaz et al., 2015). NTCP is encoded by the SLC10A1 gene (Solute Carrier family 10, member 1) located on chromosome 14. It is a transmembrane protein and involved in transport of sodium and bile acids across cellular membranes. The N-terminus of the pre-S1 domain of the large HBV envelope protein binds to NTCP, which is predominantly expressed at the basolateral membrane of hepatocytes, supporting HBV and HDV entry into hepatocytes (Ni et al., 2014, Yan et al., 2012). The missense rs2296651 variant (, S267F; substitution of serine by phenylalanine at position 267) of the SLC10A1 gene may influence HBV infection by modifying the structure of the membrane receptor, resulting in decreased susceptibility of hepatocytes to HBV/HDV infection. Several studies have shown that the S267F variant influences susceptibility to HBV infection, but not in HDV infection and that it is associated with a decreased risk of liver disease progression (Hu et al., 2016, Lee et al., 2017, Peng et al., 2015). Vietnam is highly endemic for both HBV and HDV infections (Mai et al., 2018, Nguyen et al., 2017, Sy et al., 2013). The functional role of the missense S267F variant in HBV infection has not yet been investigated, and data on whether S267F correlates with susceptibility or resistance to HDV infection is still limited. We conducted a genetic association study on the role of the NTCP S267P variant in HBV and HBV/HDV infection as well as its association with clinical progression of related liver diseases.
Materials and methods
Discussion NTCP is a member of the solute carrier family of transporters. Its major physiological function is the transport of bile acids from portal blood into hepatocytes (Claro da Silva et al., 2013, Hagenbuch and Meier, 1994). NTCP is the hepatocytic receptor for HBV and HDV (Ni et al., 2014, Yan et al., 2012); thus, genetic variation of the gene encoding NTCP might be associated with HBV and HDV susceptibility. Previous studies have indicated the clinical significance of the NTCP variant S267F only in HBV infection (Hu et al., 2016, Lee et al., 2017, Peng et al., 2015, Wang et al., 2017). Our data confirm the protective role of S267F in HBV infection, including the stages of HBV-related liver disease progression and especially also in HBV-HDV coinfection.