Genetic Polymorphism in Toll-Like Receptor 3 and Interferon Regulatory Factor 3 in Hepatitis C Virus-Infected Patients: Correlation with Liver Cirrhosis.

Host genetic factors could play a primary role in determining the risk for cirrhosis development in chronic hepatitis C virus (HCV)-infected patients. We designed this work to study the effect of single-nucleotide polymorphism (SNP) in Toll-like receptor 3 (TLR3) and interferon regulatory factor (IRF) on the risk of HCV-related cirrhosis. This study enrolled 139 Egyptian HCV-infected patients. They were divided into patients with cirrhotic (56) and noncirrhotic (83) liver. Genotyping of rs3775291 F459F (+1234C/T) and rs3775290 L412F (+1377C/T) in TLR3 and IRF3 rs2304204 (-925A/G) was performed by restriction fragment length polymorphism-polymerase chain reaction. Although there is no significant difference in genotype and allele distribution of +1377C/T of TLR3 gene between cirrhotic and noncirrhotic subjects, CC (odds ratio [OR] = 1.572, 95% confidence interval [CI]: 0.781-3.164); TT (OR = 1.463, 95% CI: 0.351-6.104) genotypes might be considered as risk factors for liver cirrhosis. On the contrary, the analysis revealed that only one genotype (CC) and one allele (C) were detected in +1234C/T SNP, with the total disappearance of CT/TT genotypes and T allele in all subjects. On the contrary, lower frequency has been found for the AG genotype of the IRF3 (-925A/G) gene in cirrhotic patients compared with noncirrhotic ones, indicating that AG is a protective genotype (OR = 0.509, 95% CI: 0.256-1.012). Our data stressed the association of AG genotype SNP in IRF3 (-925A/G) in protection against the worth outcome of HCV infection.

The Impact of Interferon-γ (IFN-γ) and IFN-γ-Inducible Protein 10 (IP-10) Genes' Polymorphism on Risk of Hepatitis C Virus-Related Liver Cirrhosis.

BACKGROUND: Today there is increasing evidence concerning the association between individual genetic polymorphisms within proinflammatory cytokines and chronic hepatitis C (CHC) severity. It has been demonstrated that polymorphisms in some genes may significantly predict HCV infected patients' susceptibility to developing liver cirrhosis or their responsiveness to the treatment. AIM: We investigated the influence of single nucleotide polymorphisms (SNPs) in Interferon (IFN-γ) and Interferon Gamma-Inducible Protein 10 (IP-10) genes on cirrhosis risk in HCV-infected patients and their association with response to various direct-acting antiviral drugs (DAAs). METHODS: IFN-γ (+874T/A, +2109A/G) and IP-10 (-135G/A, -1447A/G) genotypes were determined in 175 CHC Egyptian HCV patients (69 liver cirrhotic and 106 non-cirrhotic patients) using either single-stranded polymorphism polymerase chain reaction (SSP-PCR) or Restriction fragment length-PCR (RFLP-PCR) methods. RESULTS: IFN-γ + 874 TA, IP-10 - 135AA, and IP-10 - 1447AA and IP-10 - 1447GG genotypes are increased in patients developing liver cirrhosis compared to non-cirrhotic ones. Although, no statistical significance in their distribution was demonstrated, indicating the lack of association between these SNPs and liver cirrhosis susceptibility in HCV-infected patients. Haplotypes analysis between different loci on all selected genes showed a significant increase in AGGA and TAGA and a significant decrease in TGGA haplotypes in cirrhotic patients. Genotype frequencies at loci -135 and -1447 of IP-10 appeared to be in complete Linkage disequilibrium (LD) (D' = 0.999, r2 = 0.689). CONCLUSION: Our data support the concept that IFN-γ and IP-10 gene polymorphisms are not predictors of disease progression among Egyptian patients with HCV infection.

Interleukin-6 promotor gene polymorphisms and susceptibility to chronic hepatitis B virus in Egyptians.

AIM: To investigate the association between IL-6 polymorphisms (-174G/C, -572G/C and -597G/A) and susceptibility to chronic hepatitis B virus (CHB) infection. METHOD: Total 108 subjects with CHB infection and 102 healthy controls were enrolled in this study. IL-6 (-174G/C) was genotyped using Mutagenically separated Polymerase Chain Reaction (MS-PCR) while sequence specific primers-PCR (SSP-PCR) was used for studying -572G/C and -597G/A. IL-6 plasma level was measured using Enzyme-linked immunosorbent assay (ELISA). RESULTS: A significant increase (P < 0.01, P < 0.01, P < 0.001) in -174GG, -572GC and -597GA; respectively in the CHB group compared to control group, while -572GG genotype was significantly decreased (P < 0.01) in CHB patients. A significant increase (p < 0.01, p < 0.01) in -174 G and -597A alleles was observed in the CHB patient group; respectively. GGA haplotype is significantly increased (P < 0.05) while GCA haplotype is significantly decreased (P < 0.001) in the patient group. A moderate linkage disequilibrium (LD) (D' = 0.719, r2 = 0.474; P < 0.001) between IL-6 (-572G/C and -597G/A) was observed. A significant reduction (P < 0.01) in IL-6 plasma level in CHB patients compared to healthy controls (22.28 ±â€¯1.93 versus 32.08 ±â€¯2.41), which was negatively correlated (r = -0.216; P < 0.01) with HBV infection. CONCLUSIONS: This study pointed to the potential role of IL-6 (-174G/C, -572 G/C and -597G/A) gene polymorphisms in the susceptibility to HBV infection. Our results allow for only preliminary conclusions due to relatively small sample size. There is a need for further larger scale studies to fully examine the possible relationship between these cytokine gene polymorphisms and the development of CHB.

Association of TNF-Alpha gene polymorphisms and susceptibility to hepatitis B virus infection in Egyptians.

Tumor necrosis factor alpha (TNF-α) is one of the important cytokine in generating an immune response against hepatitis B virus (HBV). Genetic polymorphisms might influence gene transcription, leading to disturbance in cytokine production. We hypothesized that single nucleotide polymorphism (SNPs) in TNF-α gene could affect the pathogenesis of HBV. To test this hypothesis, we investigated the role of TNF-α polymorphism [-863C/A (rs1800630), -308G/A (rs1800629), -376G/A (rs1800750), -857C/T (rs1799724) and +489G/A (rs1800610)] in the susceptibility to chronic hepatitis B (CHB) infection. Polymorphisms of the TNF-α (-863C/A (rs1800630), -308G/A) were analyzed by Polymerase chain reaction sequence specific primer (PCR-SSP) while TNF-α (-376G/A, -857C/T and +489G/A) by PCR-restriction fragment length polymorphism (PCR-RFLP) in 104 patients with CHB and 104 healthy controls. The plasma level of TNF-α was measured using Enzyme-linked immunosorbent assay (ELISA). The study showed a significant increase in the frequency of -863CC, -376GA, -857CC, -857TT and +489GA genotypes and -863C, -376A, -857C, and +489A alleles in CHB patients compared to controls. In addition, CAGCG haplotype had a highest frequency in CHB patients. A strong Linkage Disequilibrium (LD) between TNF-α -863C/A (rs1800630) and -376G/A (D' = 0.7888, r2 = 0.0200); -308G/A and -857C/T (D' = 0.9213, r2 = 0.1770); -308G/A and +489G/A (D' = 0.9088, r2 = 0.1576) was demonstrated. CHB patients had significantly lower levels of TNF-α compared to controls. In conclusion, our preliminary results suggest that -863C/A (rs1800630), -308G/A, -376G/A, and +489G/A of the TNF-α gene may play a role in HBV susceptibility in Egyptians. The significant reduction in TNF-α in CHB patient was independent of any particular genotype/haplotype in TNF-α.

Association between IL-10 gene promoter polymorphism and hepatitis B viral infection in an Egyptian population.

Cytokines play critical roles in the pathogenesis of hepatitis B virus infection (HBV). This work was designed to study the effect of IL-10 gene polymorphisms (-1082G/A and -819C/T) on susceptibility of Egyptians to HBV. Genotyping was performed using single-stranded polymorphism-polymerase chain reaction in 118 Egyptian hepatitis B patients and 119 healthy controls, and IL-10 serum levels were measured using ELISA. The frequency of IL-10 -1082G/G was significantly higher in HBV patients than in healthy controls, and G/A and A/A were not significantly different between groups. The distribution of IL-10 -819 genotypes was not significantly different between the HBV and healthy control groups. Although AT was significantly different between controls and patients, the distribution of the other haplotypes was not. IL-10 levels were significantly lower among hepatitis B patients. Our data stress the importance of IL-10 gene polymorphism in HBV infection. Depending on our preliminary work, IL-10 -1082G/G may act as a host genetic factor in the susceptibility to HBV infection in Egyptians.

Transforming Growth Factor- ß 1 Gene Polymorphism (T29C) in Egyptian Patients with Hepatitis B Virus Infection: A Preliminary Study.

The interindividual variations in the capacity of transforming growth factor- ß 1 (TGF- ß 1) production have been ascribed to genetic polymorphisms in TGF- ß 1 gene. As pathogenesis of HBV has a genetic background, this preliminary study was designed to assess the impact of TGF- ß 1 (T29C) on the susceptibility of Egyptians to HBV infection. Genotyping was performed using single stranded polymorphism-polymerase chain reaction (SSP-PCR) in 65 Egyptian hepatitis B patients and 50 healthy controls. TGF- ß 1 plasma levels were measured using Enzyme-linked immunosorbent assay (ELISA). The frequency of CC genotype was significantly higher (P < 0.05) in HBV patients compared to controls. On the contrary, TC genotype did not show significant difference in both groups. TT genotype was significantly higher (P < 0.01) in controls than HBV patients. Our current preliminary data revealed that the frequency of the genotypes in the controls were within Hardy-Weinberg equilibrium (HWE) while the patients group was out of HWE (P < 0.01). TGF- ß 1 was significantly (r = -0.684; P < 0.001) deceased in the sera of patients as compared to normal subjects. Depending on our preliminary work, CC genotype may act as a host genetic factor in the susceptibility to HBV infection in Egyptians. Taken together, the current data pointed to the importance of polymorphism of TGF- ß 1 gene (T29C) in HBV infection.