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

Abstract

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.

VDR rs7975232/ApaI genetic variation predicts sustained HBsAg loss in HBeAg‐positive chronic hepatitis B patients treated with pegylated interferon

“…But some research showed contradictive results. 28,29 18 Another study in Thailand also showed genotype of CYP27B1 rs4646536 predicted the clinical outcome of CHB patients. 30 In a retrospective cohort of HBeAg-negative patients from Italy, VDR rs7975232/ApaI genotype was the independent predictor of clinical outcome.…”

“…Few studies on the association between vitamin D‐related genetic factors and response to Peg‐IFN in CHB infection have been reported yet. In a latest retrospective multicenter study, CYP2R1 rs12794714 polymorphism was determined to be genetic predictor of sustained HBeAg clearance after Peg‐IFN therapy in HBeAg‐positive CHB patients in Thailand . Another study in Thailand also showed genotype of CYP27B1 rs4646536 predicted the clinical outcome of CHB patients .…”

“…Nine single nucleotide polymorphisms (SNPs) of three critical genes in vitamin D metabolic pathway were genotyped, including VDR (rs7975232/ ApaI , rs1544410/ BsmI , rs757343/ Tru9I , rs2228570/ FokI , rs731236/ TaqI ), VDBP (rs4588, rs7041), 1α‐hydroxylase (cytochrome P450, family 27, subfamily b, polypeptide 1, CYP27B1 ) (rs10877012, rs3782130) …”

“…Nine single nucleotide polymorphisms (SNPs) of three critical genes in vitamin D metabolic pathway were genotyped, including VDR (rs7975232/ApaI, rs1544410/BsmI, rs757343/Tru9I, rs2228570/FokI, rs731236/TaqI), VDBP (rs4588, rs7041), 1α-hydroxylase (cytochrome P450, family 27, subfamily b, polypeptide 1, CYP27B1) (rs10877012, rs3782130). 14,[16][17][18][19][20][21][22][23] Human genomic DNA was extracted from 100 μL samples of peripheral whole blood using TIANamp Blood DNA Kit (Tiangen Biotech (Beijing) Co, Ltd, Beijing, China) following the manufacturer's instructions and then sent to Sangon Biotech (Shanghai) Co., Ltd (Shanghai, China) for sample amplification and detection.…”

Editorial: the durability of seroconversion of hepatitis B e antigen in the treatment of chronic hepatitis B with PEG‐interferon alfa‐2a

“…While there have been other prior studies examining the durability of HBeAg seroconversion in patients treated with PEG‐IFN, they have largely been limited by lack of long‐term follow‐up, small sample size, and/or involvement of other treatment medications . In our literature review, there was only one other study with more than 10 patients that reported follow‐up greater than 1 year (Ratnam et al), but this study was limited to just 2‐year follow‐up (Table ) …”