Associations Of The Key Gene In The Vitamin D Metabolic Pathway Genetic Variants With The Outcome Of Hepatitis B Virus Infection

Objectives1.To analysis the association of the key gene in the Vitamin D metabolic pathway genetic variants with the outcome of Hepatitis B virus infection;2.To explore the potential gene-gene or gene-environment interactions in Vitamin D metabolic pathway in relationship to the outcome of hepatitis B virus infection.MethodsWe conducted a frequency matched case-control study to investigate the association of the genetic variants in the vitamin D metabolic pathway and the outcome of hepatitis B virus infection.Potentially functional polymorphisms in the key gene of Vitamin D metabolic pathway were genotyped by Sequenom MassARRAY methods.χ2 test was used to examin differences between groups in distributions of age,sex,smoking,drink,genotyping.The association between single variant and the outcome of hepatitis B virus infection was estimated as odds ratio(OR)and 95% confidence interval(95% CI)calculated by logistic regression under heterozygote,homozygous mutation,dominant and recessive genetic models.Additionally,A comprehensive strategy was applied to systematically explore the potential gene-gene and gene-environment interactions by combining Logistic regression analysis and multifactor dimensionality reduction approaches.Results1.In the association of single variant and the outcome of hepatitis B virus infection analisis,the multvariate logistic regression analysis showed that RXRB rs2076310 was associated with the self-limiting clear after HBV infection,rs2076310 GA genotype,dominant genetic models were associated with decrease risk of HBV infection(OR=0.73,95% CI=0.57-0.95,OR=0.73,95% CI=0.57-0.93).rs2248359 in CYP24A1 was associated with the risk of hepatocellular carcinoma after HBV infection under CT genotype and dominant genetic models(OR=1.49,95% CI=1.14-1.96,OR=1.43,95% CI=1.11-1.85).rs11574012 in VDR showed a decrease risk of HBV related hepatocellular carcinoma under AG genotype and dominant genetic models(OR=0.62,95% CI=0.44-0.88,OR=0.66,95%CI=0.51-0.85),similarly rs2076310 was also associated with HBV related hepatocellular carcinoma under GA genotype and dominant models(OR=0.66,95% CI=0.504-0.86OR=0.66,95% CI=0.51-0.85,OR=0.66,95% CI=0.51-0.85).Compared with self-limited persons,rs11574012 AG and dominant models were associated with decreased risk of HBV infection and HBV related hepatocellular carcinoma(OR=0.745,95% CI=0.55-0.99,OR=0.73,95% CI=0.55-0.98).rs2076310 in RXRB remained association with decreased risk of HBV infection and HBV related hepatocellular carcinoma in AA genotype heterozygous and dominant models(OR=0.71,95% CI=0.57-0.88,OR=0.66,95%CI=0.47-0.92,OR=0.70,95% CI=0.57-0.86).2.In the haplotype analysis,TCTCATG built by VDR was associated with decreased risk of hepatocellular carcinoma after HBV infected(OR=0.64,95% CI=0.43-0.96),TCTCGTG haplotype was associated with decreased risk of HBV related hepatocellular carcinoma(OR=0.63,95% CI=0.41-0.95).3.We assessed pair-wise interaction between among 3 promising variants,smoking,drinking,antiviral therapy,and history of tumor family by logistic regression.Compared with self-limited persons who has family history of malignancy and rs11574012 AA carrier had a low risk of HBV infection 0.34 times than those who was non-smokers and AG/GG carrier(95% CI=0.20-0.58).Besides,a significant interaction between rs11574012 and smoking was found.Compared with chronic HBV infection people who was smoking and rs11574012 AA carrier had a risk of HBV related hepatocellular carcinoma 4.91 times than those who was non-smokers and AG/GG carrier(95% CI=2.91-8.29)with multiplicative interaction(Pmult=0.018),but not additive interaction.Additionally,rs2248359 and familyhistory of malignancy showed interaction in HBV related hepatocellular carcinoma vs.HBV carrier.Compared with chronic HBV infection people who was smoking and rs2248359 CT/TT carrier had a risk of HBV related hepatocellular carcinoma 8.171 times than those who was non-smokers and CC carrier(95% CI=4.61-14.47)with multiplicative interaction(Pmult=0.008).Conclusions1.rs11574012 in VDR and rs2076310 in RXRB were the most important genetic variants in Vitamin D metabolic pathway for the susceptibility to the outcome of HBV infection,mutant allele T of rs2248359 in CYP24A1 was associated with increased risk of HBV related hepatocellular carcinoma.2.The rs11574012 variant in VDR could interaction between family history of malignancy so that affecting the outcome of HBV infection.rs11574012 and smoking,rs2248359 and family history of malignancy may play important role in the development of hepatocellular carcinoma after HBV infection.