Impact of CYP2R1, CYP27A1 and CYP27B1 genetic polymorphisms controlling vitamin D metabolism on susceptibility to hepatitis C virus infection in a high-risk Chinese population.

CYP27A1, CYP2R1 and CYP27B1 hydroxylases are involved in the synthesis of 1, 25-hydroxyvitamin D3, which plays a role in the immune regulation and pathogenesis of hepatitis C virus (HCV) infection. The aim of the present study was to investigate the relationships between polymorphisms in vitamin D pathway genes and HCV infection outcomes in a Chinese population. Nine single-nucleotide polymorphisms (SNPs) of CYP27A1, CYP2R1 and CYP27B1 were genotyped in a high-risk Chinese population. The distributions of these SNPs were compared among groups with different outcomes of HCV infection, including 863 cases of persistent HCV infection, 524 cases of spontaneous clearance, and 1079 uninfected controls. The results showed that the CYP2R1 rs12794714-G, rs10741657-A, rs1562902-C, and rs10766197-G alleles were significantly associated with increased susceptibility to HCV infection (all PFDR < 0.05, in additive/dominant models), and the combined effect of the four unfavorable alleles was related to an elevated risk of HCV infection in a locus-dosage manner (Ptrend = 0.008). Moreover, haplotype analysis suggested that, compared with the most frequent haplotype (Ars12794714Grs10741657Trs1562902Ars10766197), the haplotype containing four unfavorable alleles, GACG, was associated with a higher risk of HCV infection. The results of our study suggest that genetic variants in CYP2R1 may be biomarkers for predicting the susceptibility to HCV infection in the Chinese population.

CYP24A1 genetic variants in the vitamin D metabolic pathway are involved in the outcomes of hepatitis C virus infection among high-risk Chinese population.

BACKGROUND AND AIMS: It has been demonstrated that 1,25-hydroxyvitamin-D3-24-hydroxylase, encoded by CYP24A1 gene, is a key enzyme that neutralizes the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in response to hepatitis C virus (HCV) infection. This study aimed to investigate whether CYP24A1 genetic variation is associated with HCV infection outcomes. METHODS: 848 HCV chronically infected subjects, 507 natural clearance subjects, and 1017 uninfected controls were enrolled. Nine single nucleotide polymorphisms (SNPs) in theCYP24A1 gene were genotyped using the Sequenom MassARRAY platform. RESULTS: After adjusting for age, gender, and routes of infection, logistic regression analyses showed that rs6013897-A was associated with an elevated risk of HCV infection (P<0.05). In addition, this study has also demonstrated that rs6068816-T significantly reduced the risk of chronic HCV infection, while rs3787557-C, rs6022999-G, and rs2248359-T significantly increased the risk of chronic HCV infection (all P<0.05). Haplotype analysis suggested that, compared to the most frequent Trs6068816Trs3787557Ars6022999Crs2248359 haplotype, the CTGT haplotype (adjusted OR=1.376, 95% CI=1.092-1.735, P=0.007) and CCAC haplotype (adjusted OR=1.483, 95% CI=1.139-1.929, P=0.003) were associated with an increased risk of chronic HCV infection. CONCLUSION: These findings indicate that SNPs in CYP24A1 gene may contribute to the risk of HCV infection and chronic HCV infection among a high-risk Chinese population.

Genetic variants in IFIH1 and DDX58 influence hepatitis C virus clearance in Chinese Han population.

AIMS: To investigate the association between two RIG-I-like receptor gene polymorphisms and hepatitis C virus (HCV) infection in Chinese Han population. METHODS: The current study genotyped two selected SNPs (IFIH1 rs3747517 and DDX58 rs9695310) using TaqMan allelic discrimination assay to assess their association with the susceptibility and clinical outcome of HCV infection among 3065 participants (1545 non-HCV infection individuals, 568 spontaneous HCV clearance cases, and 952 persistent infection patients). RESULTS: IFIH1 rs3747517 (dominant model: Adjusted odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.07-1.68; P = 0.009) and DDX58 rs9695310 (dominant model: Adjusted OR = 1.43, 95% CI = 1.15-1.78; P = 0.001) were associated with chronic hepatitis C (CHC). And the risk of CHC increased when people were carrying more unfavorable rs3747517-GA/AA and rs9695310-GC/CC genotypes from zero to two with the chronic rates of 56.72%, 59.38%, and 69.01%, respectively (Ptrend < 0.001). CONCLUSION: Genetic variations at IFIH1 rs3747517 and DDX58 rs9695310 were independent predictors of chronic hepatitis C in Chinese Han population.

Vitamin D binding protein polymorphisms influence susceptibility to hepatitis C virus infection in a high-risk Chinese population.

Vitamin D binding protein (VDBP) plays an important role in the immune modulation and pathogenesis of hepatitis C viral (HCV) infection by influencing serum vitamin D levels. The present study aims to evaluate the association of VDBP genetic polymorphisms with susceptibility to and chronicity of HCV infection in a high-risk Chinese population. Seven genetic variants in the VDBP gene were genotyped in a case-control study of 886 patients with HCV persistent infection, 539 subjects with spontaneous clearance, and 1081 uninfected controls. Logistic regression analysis was used to assess the effects of these variants on HCV infection outcomes. The results showed that two variants rs7041-G and rs3733359-T alleles were significantly associated with increased susceptibility of HCV infection, and the combined effect of the two unfavorable alleles was related to an elevated risk of HCV infection in a locus-dosage manner (Ptrend = 8.16 × 10-4). Interaction analysis manifested that rs7041-GT/GG and rs3733359-CT/TT jointly increased risk of HCV infection. Moreover, haplotype analysis suggested that compared with the most frequent TC haplotype, the haplotype carrying GT indicated a risk effect of HCV infection [odds ratio (OR) = 1.464]. However, no significant associations were observed for the other five variants. These findings implied that VDBP rs7041-G and rs3733359-T variants may contribute to increased susceptibility to HCV infection in a high-risk Chinese population.

Genetic variation on the NFKB1 genes associates with the outcomes of HCV infection among Chinese Han population.

AIM: To investigate whether nuclear factor-kappa B1 (NFKB1) gene polymorphisms are associated with the outcomes of hepatitis C virus (HCV) infection in a Chinese high-risk population. METHODS: In this case-control study, 984 HCV-uninfected controls, 221 infected individuals with spontaneous HCV clearance, and 456 with persistent HCV infection were enrolled. Rs28362491 and rs72696119 were genotyped using the ABI TaqMan allelic discrimination assay. The functional annotation of the identified single nucleotide polymorphisms (SNPs) were further evaluated by bioinformatics analysis. RESULTS: Significant differences were observed among the three groups (P < 0.001) in terms of the frequency of rs28362491 SNP. In logistic regression analysis, rs28362491-ATTG deleted (D) was associated with a significantly increased risk of HCV infection compared to the major-type rs28362491-ATTG inserted (I) (dominant model: adjusted OR = 1.332, 95% CI = 1.059-1.674, P = 0.014; additive model: adjusted OR = 1.181, 95% CI = 1.021-1.367, P = 0.025), after adjusting for age, gender, and route of infection. Based on the in silico prediction, the RegulomeDB score for SNP rs28362491 was 3a, indicating that it can potentially regulate the transcription and expression of NFKB1 gene. CONCLUSION: NFKB1 rs28362491-D allele was functionally associated with the increased risk of susceptibility to HCV infection in the Chinese Han population.