Vitamin D-Binding protein Gene Polymorphism Predicts Pegylated Interferon-Related HBsAg Seroclearance in HBeAg-Negative Thai Chronic Hepatitis B Patients: A Multicentre Study

Background: Vitamin D deficiency is related to poor clinical outcomes in patients with chronic hepatitis B virus (HBV) infection. Methods: We aimed to investigate the association between the genetic variants in the vitamin D metabolic pathway and the response to pegylated interferon (Peg-IFN) therapy in patients with HBeAg-negative chronic HBV infection. One hundred seven patients treated with Peg-IFN for 48 weeks were selected from 13 specialty hospitals. Eight genotypes of vitamin D cascade genes, including CYP27B1 (rs10877012), DHCR7 (rs12785878), CYP2R1 (rs2060793, rs12794714) and GC (rs4588, rs7041, rs222020, rs2282679), were found. Results: Eighty-two patients (83.7%) were infected with HBV genotype C. Eight patients had compensated liver cirrhosis (8.7%). At 24 weeks after treatment discontinuation, 41 patients (42.3%) achieved sustained treatment response, 53 (55.2%) obtained HBV DNA<2,000 IU/ml, 6 (5.6%) gained HBsAg seroclearance, 2 (1.9%) had HBsAg seroconversion and 69 (64.5%) exhibited alanine aminotransferase (ALT) normalization. Multivariate analysis revealed that baseline HBsAg level (OR =0.06, 95% CI: 0.08-0.49, p=0.008) and the GC rs222020 TT genotype (OR=17.72, 95% CI: 1.07-294.38, p=0.04) independently predicted sustained HBsAg seroclearance. In addition, this genotype was a predictor for normalization of ALT (OR=4.61, 95%CI: 1.59-13.40, p=0.005) after therapy. The HBsAg levels at baseline and during and post-treatment tended to be reduced with the GC rs222020 TT compared with the non-TT genotypes. The other studied polymorphisms were not associated with treatment response. Conclusions: The GC rs222020 TT genotype, which is a variant in the vitamin D-binding protein gene, could identify HBeAg-negative patients who have a high probability to achieve HBsAg clearance and ALT normalization after treatment with Peg-IFN.

Association of the S267F variant on NTCP gene and treatment response to pegylated interferon in patients with chronic hepatitis B: a multicentre study.

BACKGROUND: 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.

Genetic variation in the vitamin D pathway CYP2R1 gene predicts sustained HBeAg seroconversion in chronic hepatitis B patients treated with pegylated interferon: A multicenter study.

Evidence of a role of vitamin D in the immune system is increasing. Low serum vitamin D is associated with increased hepatitis B virus replication. Genome-wide association study (GWAS) data has revealed a number of the single nucleotide polymorphisms (SNPs) within the vitamin D synthetic pathway that affect vitamin D functions. We aimed to determine the association between SNPs in the vitamin D gene cascade and response to pegylated interferon (PegIFN) therapy in hepatitis B e-antigen (HBeAg)-positive patients. One hundred and eleven patients treated for 48 weeks with PegIFN-alfa 2a at 13 hospitals were retrospectively evaluated. Thirteen SNPs derived from vitamin D cascade-related genes, including DHCR7 (rs12785878), CYP27B1 (rs10877012), CYP2R1 (rs2060793, rs12794714), GC (rs4588, rs7041, rs222020, rs2282679), and VDR (FokI, BsmI, Tru9I, ApaI, TaqI), were genotyped. Thirty-one patients (27.9%) seroconverted to HBeAg after 24 weeks of treatment. Multivariate analysis found pretreatment qHBsAg <10,000 IU/mL (OR = 7.73, 95% CI: 2.36-25.31, P = 0.001), CYP2R1 rs12794714 TT genotype (OR = 4.16, 95% CI: 1.07-16.25, P = 0.04), and baseline ALT >2 times the upper limit of normal (OR = 3.83, 95% CI: 1.31-11.22, P = 0.014) predicted sustained HBeAg seroconversion after completion of PegIFN treatment. HBV DNA during study period tended to be lower with the rs12794714 CYP2R1 TT than the non-TT genotype. The rs12794714 CYP2R1 polymorphism may be a useful pretreatment factor predictive of sustained HBeAg seroconversion after PegIFN therapy. This study provides evidence that not only vitamin D level but also genetic variation of CYP2R1 in the vitamin D cascade influences host immune response in chronic HBV infection.