Association of Genetic Variation of Sodium Taurocholate Cotransporting Polypeptide with Chronic Hepatitis B Virus Infection

Abstract

Background: Sodium taurocholate cotransporting polypeptide (NTCP) plays an important role in the enterohepatic circulation of bile acids and hepatocyte function and was recently proposed to be a functional receptor for hepatitis B virus (HBV). Objective: This study investigated the association of the functional polymorphism c.800C > T (p.S267F) (rs2296651) of the NTCP gene with HBV infection. Methods: The study included 244 patients with chronic HBV infection, 76 HBV infection resolvers, and 113 healthy controls. The polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. Results: The distribution of the genotype and allele frequency of rs2296651 polymorphism was significantly different among the HBV patients, HBV infection resolvers, and healthy controls ( p = 0.034 and p = 0.039, respectively). The frequency of genotype CT in HBV patients was significantly higher than that in healthy controls (11.9% vs. 4.4%, p = 0.026, odds ratios [OR] = 2.913, 95% confidence intervals [95% CI] = 1.097-7.738). The frequency of allele T in HBV patients was also significantly higher than that in healthy controls (5.9% vs. 2.2%, p = 0.029, OR = 2.793, 95% CI = 1.067-7.312). The frequency of genotype CT and allele T in HBV patients was higher than that in HBV infection resolvers although the difference was not significant. The genotype and allele frequency between infection resolvers and healthy controls and between HBV patients with different clinical diseases had no significant difference. Conclusion: These findings suggest that the rs2296651 polymorphism may predispose the susceptibility to and chronicity of HBV infection.

Hepatitis B virus infection in Taiwan: The role of NTCP rs2296651 variant in relation to sex

“…Host genetics significantly contributes to the clinical outcome of HBV infection. NTCP plays an important role in the enterohepatic circulation of bile acids and also serves as a receptor for hepatitis B and D viruses . However, a previous study has reported that common variants in NTCP might not influence the expression level of SLC10A1 at transcriptional regulation, hence may not be associated with HBV susceptibility .…”

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

“…However, the distribution of the minor allele was not in accordance with the Hardy-Weinberg equilibrium (p<0.001), due to less individuals being homozygous for S267F than the expected value. A study of limited number of subjects showed that in the Chinese Han population the S267F variant was associated with HBV infection (OR 2.91 (95% CI 1.10 to 7.74), p=0.03)19; while a larger cohort study of 1899 patients with HBV showed that S267F was associated with resistance to CHB (OR (95% CI) 0.36 (0.29 to 0.44) and 0.16 (0.06 to 0.40) for heterozygotes and homozygotes, respectively) 20. Our results showed that S267F AA homozygotes were strongly associated with HBsAg-seronegativity (OR 0.13 (95% CI 0.05 to 0.34), p<0.001), which support the findings of the later report.…”

“…Previous association studies on NTCP S267F and HBV infection have yielded conflicting results,19 20 and the role of this variant in cirrhosis and HCC remains unclear. In addition, no studies have focused on identifying genetic variants in the key functional region between aa157 and 165 of NTCP among patients with CHB.…”

One small SNP for receptor virus entry, one giant leap for hepatitis B?

“…Substitution of a phenylalanine for a serine at position 267 (p.Ser267Phe ( the S267 variant) (c.800G>A, rs 2296651)14 on SLC101A has been identified leading to normal cell-surface expression of NTCP but with complete loss of bile-salt uptake (figure 1). 12 14 15 The S267F allele is found in East Asian populations,13 with a similar prevalence reported in Chinese Americans 16. The importance of the S267F-NTCP variant on the natural history of HBV to date has not been fully established.…”

“…The importance of the S267F-NTCP variant on the natural history of HBV to date has not been fully established. The first study in Chinese Han individuals16 surprisingly found that the S267F variant was associated with an increased risk of HBV infection; however, in a much larger study of 1899 patients with HBV of similar ethnicity, the S267F allele was associated with resistance to chronic HBV and a lower incidence of acute-on-chronic liver failure 17. Notably, despite its functional effects, S267F heterozygotes and even homozygotes do not have an obvious disease phenotype independent of HBV 15…”