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 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

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

<div><p>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 <i>DHCR7</i> (rs12785878), <i>CYP27B1</i> (rs10877012), <i>CYP2R1</i> (rs2060793, rs12794714), <i>GC</i> (rs4588, rs7041, rs222020, rs2282679), and <i>VDR</i> (<i>Fok</i>I, <i>Bsm</i>I, <i>Tru</i>9I, <i>Apa</i>I, <i>Taq</i>I), 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, <i>P</i> = 0.001), <i>CYP2R1</i> rs12794714 TT genotype (OR = 4.16, 95% CI: 1.07–16.25, <i>P</i> = 0.04), and baseline ALT >2 times the upper limit of normal (OR = 3.83, 95% CI: 1.31–11.22, <i>P</i> = 0.014) predicted sustained HBeAg seroconversion after completion of PegIFN treatment. HBV DNA during study period tended to be lower with the rs12794714 <i>CYP2R1</i> TT than the non-TT genotype. The rs12794714 <i>CYP2R1</i> 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 <i>CYP2R1</i> in the vitamin D cascade influences host immune response in chronic HBV infection.</p></div

Mean HBV DNA and qHBsAg during PegIFN therapy in patients stratified by <i>CYP2R1</i> rs12794714 TT and non-TT genotype.

<p>Mean HBV DNA and qHBsAg during PegIFN therapy in patients stratified by <i>CYP2R1</i> rs12794714 TT and non-TT genotype.</p

Baseline characteristics of patients with HBeAg-positive chronic hepatitis B infection after 48 weeks of PegIFN therapy.

<p>Baseline characteristics of patients with HBeAg-positive chronic hepatitis B infection after 48 weeks of PegIFN therapy.</p

Outcomes in patients with HBeAg-positive CHB infection stratified by HBV genotype after completing 24 weeks of PegIFN treatment.

<p>Outcomes in patients with HBeAg-positive CHB infection stratified by HBV genotype after completing 24 weeks of PegIFN treatment.</p

Genotype frequencies of <i>DHCR7</i>, <i>CYP27B1</i>, <i>CYP2R1</i>, <i>GC</i> and <i>VDR</i> in HBeAg-positive chronic hepatitis B patients treated with PegIFN for 48 weeks.

<p>Genotype frequencies of <i>DHCR7</i>, <i>CYP27B1</i>, <i>CYP2R1</i>, <i>GC</i> and <i>VDR</i> in HBeAg-positive chronic hepatitis B patients treated with PegIFN for 48 weeks.</p