Interaction effects among IFN-γ+874, IL-2-330, IL-10-1082, IL-10-592 and IL-4-589 polymorphisms on the clinical progression of subjects infected with hepatitis B virus and/or hepatitis C virus: a retrospective nested case-control study.

BACKGROUND: The natural outcomes of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections vary considerably among individuals The infection may heal naturally, or patients may succumb to chronic liver diseases, including chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The mechanism is not fully understood. OBJECTIVES: To evaluate the interaction among four single nucleotide polymorphisms (SNPs) and their influence on different clinical outcomes. METHODS: 277 individuals infected with HBV and/or HCV, including 81 patients with chronic hepatitis B and C, 122 asymptomatic HBV and/or HCV carriers and 74 controls who cleared HBV and HCV spontaneously, were involved in this study. The SNPs of four genes (rs2069762/-330 G/T of IL-2, rs2430561/+874A>T of IFN-γ, rs1800896/-1082G>A and rs1800872/-592C>A of IL-10 and rs2243250/-589C>T of IL-4) were analysed using restriction fragment length polymorphism-polymerase chain reaction or sequence-specific primer PCR. The gene-gene interactions were assessed using the multifactor-dimensionality reduction method. RESULTS: Interleukin (IL)-10-592 AC and IL-4-589 CC/CT showed a synergistic effect on liver inflammatory injury (p<0.01), whereas interferon (IFN)-γ+874 AA and IL-2-330 TT had a synergistic impact (p<0.05). IFN-γ+874 AA and IL-10-1082 AA had an antagonistic effect (p<0.01) on the clinical progression, including asymptomatic HBV and HCV carriers and chronic hepatitis. IL-2-330 TT and IL-10-1082 AA synergistically influenced the clinical outcome (p<0.05). IFN-γ+874 AA, IL-2-330 TT and IL-10-1082 AA interactively affected the clinical outcome including asymptomatic HBV and HCV carriers and chronic hepatitis (p<0.05). CONCLUSIONS: Interactions among polymorphisms of IFN-γ+874 AA, IL-2-330 TT, IL-10-1082 AA, IL10--592 AC and IL-4-589 CC/CT significantly influenced the clinical progression of the subjects with HBV and/or HCV infection.

[Relations between IL-2-330 polymorphisms and the outcome of hepatitis B and/or hepatitis C virus infection].

OBJECTIVE: To study the relationship between polymorphisms in interleukin-2 gene at position -330 (IL-2-330) and the clinical outcome of hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection. METHODS: 277 subjects were recruited including 79 chronic HCV co-HBV infection, 55 chronic HCV infection, 69 chronic HBV infection and 74 controls. Single nucleotide polymorphisms of IL-2-330 was investigated by restricted fragment long polymorphism-PCR (RFLP-PCR). Hepatocellular injury, as revealed by alanine aminotransferase (ALT) was detected by Beckman LX-20 analyzer. The presence of hepatitis C viral particles in serum was determined by RT-nPCR. RESULTS: (1) IL-2-330 polymorphisms showed close association with persistent HBV and/or HCV infection. IL-2-330 TT was associated with an increased risk, but IL-2-330 GG with a reduced risk of persistent HBV and/or HCV infection (χ(2) = 14.24, P = 0.03) with ORs (95%CI) as 7.14 (2.13 - 23.81), 3.46 (1.17 - 10.02) and 2.93 (1.15 - 7.46) respectively. However, IL-2-330 TT/GG did not significantly differ between patients with HBV and/or HCV infection (χ(2) = 2.09, P = 0.72). IL-2-330 T allele was associated with an increased risk, but the -330G allele was associated with a reduced risk of chronic HBV/HCV infection (χ(2) = 12.33, P = 0.01), with ORs (95%CI) as 2.26 (1.39 - 3.69), 1.82(1.09 - 3.03) and 1.73 (1.10-2.73) respectively. (2) IL-2-330 polymorphisms showed significant association with the outcome of HBV and HCV infection (χ(2) = 13.52, P = 0.04). IL-2-330 TT was associated with an increased risk, but -330 GG with a reduced risk of mild CH, moderate/severe CH, and cirrhosis. The ORs (95%CI) appeared to be 3.33 (1.75 - 6.32), 3.31 (1.75 - 6.26), 11.23 (3.09 - 40.76) respectively. IL-2-330 T allele was associated with an increased risk, but the -330 G allele was associated with a reduced risk of mild CH, moderate/severe CH and cirrhosis (χ(2) = 12.32, P = 0.01), with ORs as 1.86 (1.32 - 2.63), 1.71 (1.27 - 2.31) and 2.77 (1.57 - 4.89) respectively. (3) The polymorphisms of IL-2-330 showed no association with HCV RNA replication (χ(2) = 0.83, P = 0.66; χ(2) = 0.20, P = 0.66). The polymorphisms of IL-2-330 were not significantly associated with abnormal ALT (χ(2) = 1.10, P = 0.58; χ(2) = 0.08, P = 0.78). CONCLUSION: These results suggested that IL-2-330 TT/T was associated with an increased risk, but IL-2-330 GG/G was associated with reduced risk of persistent HBV and/or HCV infection, and with the development of mild CH, moderated/severe CH, and cirrhosis.

[Association between IFN-gamma+874 polymorphisms and the clinical outcomes of hepatitis B and/or hepatitis C virus infection.].

OBJECTIVE: To explore the association between polymorphisms of interferon-gamma gene intron 1 at position +874 (IFN-gamma+874) gene and the susceptibility of HBV and/or HCV infection with different clinical outcomes. METHODS: IFN-gamma+874 gene SNP were detected in 277 subjects including 79 chronic HBV/HCV coinfections, 69 individuals only with HBV infection, 55 individuals only with HCV infection and 74 controls, by sequence specific primers-PCR (SSP-PCR). Hepatocellular injury as suggested by alanine aminotransferase (ALT) was detected by Beckman LX-20. The status of viral particles in serum was determined by RT-nPCR. The possible association of the polymorphism of IFN-gamma+874 with the susceptibility of HBV and/or HCV infection and the outcome of these infections were analyzed. RESULTS: (1) IFN-gamma+874 AA frequency in individuals with chronic HBV, HCV, HBV/HCV coinfections were significant higher than that in controls (chi(2) = 16.15, P = 0.01);OR (95%CI) of IFN-gamma+874 AA in chronic infection with HBV, HCV, HBV/HCV coinfections appeared to be 2.70 (1.24 - 5.92), 3.22 (1.43 - 7.25) and 4.02 (1.88 - 8.55) compared with +874 TA. No significant differences were found among HBV, HCV, HBV/HCV coinfections (chi(2) = 1.97, P = 0.73). There were no significant association of IFN-gamma+874 A/T allele frequency with HBV and/or with HCV infection (chi(2) = 4.87, P = 0.18). (2) The clinical outcomes of mild chronic hepatitis (CH), moderate/severe CH and cirrhosis with HBV and/or HCV infection were associated with IFN-gamma+874 AA [chi(2) = 14.17, P = 0.03; OR = 3.09 (1.51 - 6.33), 3.85 (1.70 - 8.70), 3.14 (1.08 - 9.17)]. No significant relationships were found between IFN-gamma+874 A/T allele frequency and the clinical outcome of HBV/HCV infection (chi(2) = 6.07, P = 0.11). (3) There were no significant associations of IFN-gamma+874 genotype/allele frequency with HCV duplication (chi(2) = 2.36, P = 0.31). (4) There were no significant associations of IFN-gamma+874 genotype/allele frequency with abnormal ALT (chi(2) = 0.15, P = 0.93). CONCLUSION: These results suggested that polymorphisms in the IFN-gamma+874 had some influence on chronic HCV and/or HBV infection, and on the outcome of HCV and/or HBV infections. IFN-gamma+874 AA genotype and T allele were possible risk to chronic HBV and/or HCV infections and to the outcomes of HBV and/or HCV infection. However, IFN-gamma+874 TA genotype might serve as possible protective factors to them.

Polymorphisms of some cytokines and chronic hepatitis B and C virus infection.

AIM: To study the relationship between the polymorphisms in some cytokines and the outcome of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. METHODS: Samples were obtained from 203 patients infected with HBV and/or HCV while donating plasma in 1987, and 74 controls were obtained from a rural area of North China. Antibodies to HBV or HCV antigens were detected by enzyme-linked immunoassay. The presence of viral particles in the serum was determined by nested reverse-transcriptase polymerase chain reaction (PCR). Hepatocellular injury, as revealed by alanine aminotransferase (ALT) and aspartate aminotransferase level, was detected by a Beckman LX-20 analyzer. DNA was extracted from blood cells. Then, the single nucleotide polymorphisms of IL-2-330, IFN-gamma+874, IL-10-1082/-592 and IL-4-589 were investigated by restriction fragment length polymorphism-PCR or sequence specific primer-PCR. RESULTS: Persistent infection with HBV, HCV, and HBV/HCV coinfection was associated with IL-2-330 TT genotype and T allele, IFN-gamma+874 AA genotype, and IL-10-1082 AA genotype. The clinical outcome of HBV and/or HCV infection was associated with IL-2-330 TT genotype and T allele, IFN-gamma+874 AA genotype, and IL-10-1082 AA genotype. IL-2-330 GG genotype frequency showed a negative correlation with clinical progression, IL-10-1082 AA genotype frequency showed a positive correlation and IL-10-1082 AG genotype frequency showed a negative correlation with clinical progression. HCV RNA positive expression was associated with IL-10-1082 AA genotype and the A allele frequency. Abnormal serum ALT level was associated with IL-10-592 AC genotype frequency and IL-4-589 CC genotype, CT genotype, and the C allele. CONCLUSION: These results suggest that polymorphisms in some cytokine genes influence persistent HBV and HCV infection, clinical outcome, HCV replication, and liver damage.