TNF-α and IL-10 polymorphisms increase the risk to hepatocellular carcinoma in HCV infected individuals.

Hepatitis C virus (HCV) is the major cause of hepatocellular carcinoma (HCC). The risk to develop HCC increases with the severity of liver inflammation and hepatic fibrosis. It is believed that a balance between the releases of pro- and anti-inflammatory cytokines will determine the clinical course of HCV and the risk to develop HCC. The inteleukin-10 (IL-10) and the tumor necrosis factor alpha (TNF-α) play key roles in the Th1 and Th2 balance during the inflammatory response against HCV. The aim of the present study was to investigate the association between polymorphisms in TNF-α -308 G>A (rs1800629), IL-10 -1082 G>A (rs1800896) and -819/-592 (rs1800871/rs1800872) with HCC risk in individuals with HCV. The present study evaluated 388 chronic HCV patients. Polymorphisms were determined by real-time PCR. Diplotypes associated with low IL-10 production and the TNF-α GG genotype were significantly associated with HCC occurrence after multivariate logistic regression analysis (P = 0.027 and P = 0.029, respectively). Additionally, the IL-10 -819 (-592) TT (AA) genotype was significantly associated with multiple nodules and HCC severity according to BCLC staging (P = 0.044 and P = 0.025, respectively). Patients carrying low production haplotypes of IL-10 and the TNF-α GG genotype have higher risk to develop HCC. J. Med. Virol. 88:1587-1595, 2016. © 2016 Wiley Periodicals, Inc.

Two sides of a coin: GG genotype of C7 provides protection against fibrosis severity while showing a higher risk for hepatocellular carcinoma in patients with hepatitis C.

The complement system (CS) is a key element of immunity against pathogens but also seems to influence other events, such as tumorigenesis and tissue repair. Complement component 7 (C7) is a key component of the lytic pathway of CS, leading to the formation of the membrane attack complex (MAC). This study aimed to investigate the existence of the association of a polymorphism in the C7 gene, rs1063499, with hepatic fibrosis and the occurrence of hepatocellular carcinoma (HCC) in patients with hepatitis C. We analyzed 456 samples from patients with chronic hepatitis C. Real-time PCR was used for allelic discrimination. Patients were classified by their METAVIR score as F1 (n = 100), F2 (n = 83), F3 (n = 101) or F4 (n = 66); 106 patients were diagnosed with HCC. Patients carrying the G/G genotype of C7 had a lower chance of developing severe fibrosis in the recessive model (p = 0.042; OR: 0.65 95% CI 0.41-1.02). However, the G/G genotype frequency was higher in patients with HCC (P = 0.01; OR: 2.07 95% CI 1.20-3.53) and in those with larger tumors (p = 0.04). The G/G C7 genotype seems to be a protective factor against advanced fibrosis; however, it was associated with a higher risk of HCC and the occurrence of larger hepatic nodules, suggesting the involvement of C7 in the physiopathogenesis of HCC and fibrosis in patients with hepatitis C virus (HCV).

Low IL10 serum levels as key factor for predicting the sustained virological response to IFNα/ribavirin in Brazilian patients with HCV carrying IL28B CT/TT genotype.

PROPOSE: IL28B polymorphisms rs12979860 CC genotype was associated to protection of HCV infection and sustained virological response (SVR) in HCV infected patients treated with pegIFNα/ribavirin (IFNα/RIB), however, this polymorphism frequency varies depending on genetic components. Studies with larger number of Brazilian individuals, determining IL28B polymorphisms is lacking. Regarding to treatment response, the levels of IL10 seem to influence response to IFNα/RIB therapy. Thus, the IL28B polymorphism frequency was investigated in health controls and infected HCV patients, as well as, in patients who reach SVR vs Non-SVR. Also, to gain insight into the interplay between IL28B genotypes, IL10 levels and therapy response, a subgroup of genotyped HCV patients SVR and Non-SVR were analyzed regarding the IL10 production. METHODS: It was enrolled 487 HCV infected patients and 234 healthy individuals. Patients with response to IFNα/RIB were classified as SVR (n = 81) and Non-SVR (n = 123). TAQMAN probes were used for genotyping the SNP rs12979860, resulting in CC, CT or TT genotypes. In one hundred one patients, the levels IL10 were measured at week 4 of IFNα/RIB. RESULTS: CC genotype was associated to SVR (p = 0.029) and its frequency was higher in healthy individuals vs patients (p = 0.02). Patients carrying CT/TT with IL10<10 pg/mL, had a chance of 2.72 to achieve SVR in multivariate model (p = 0.043). CONCLUSION: CC genotype was associated to SVR and protection to HCV infection. Moreover, IL28B genotyping and IL10 serum levels could be further explored as a useful algorithm for identify the CT/TT SVR patients.

Plasma myeloperoxidase levels correlate with hepatocellular carcinoma in chronic hepatitis C.

Myeloperoxidase (MPO) is an enzyme responsible for generating hypochlorous acid and reactive oxidants that may lead to liver injury and cancer in hepatitis C (HCV) infection. MPO expression level is regulated by a polymorphism in the promoter region -463 of MPO gene. In the current study, MPO plasma levels and the G-463A MPO polymorphism were determined in 158 chronically HCV infected patients with and without hepatocellular carcinoma (HCC). MPO plasma levels were determined using a commercially ELISA kit. The G-463A MPO polymorphism was accessed by real time PCR using TaqMan probes. The MPO plasma levels of patients with HCV-HCC were higher in comparison to patients with chronic hepatitis or with those patients with severe fibrosis (p=0.01 and p=0.04, respectively). The MPO G-463A polymorphism was not associated with HCV outcome. These findings suggest MPO levels monitoring may be a potential biological marker to HCC screening in patients with HCV.