Tumor necrosis factor-alpha-308G/A polymorphism and risk of hepatocellular carcinoma in hepatitis C virus-infected patients

Abstract

Tumor necrosis factor-alpha (TNF-α) is an important cytokine in generating an immune response against infection with hepatitis C virus (HCV). The functions of TNF-α may be altered by single-nucleotide polymorphisms (SNPs) in its gene structure. We hypothesized that SNPs in TNF-α may be important in determining the outcome of an HCV infection. To test this hypothesis, we investigated the role of the polymorphism -308G/A, which is located in the promoter region of the TNF-α gene, in the progression of HCV infection in Egyptian patients using a quantitative real-time polymerase chain reaction (qRT-PCR). The distribution of this polymorphism and its impact on the serum level of TNF-α was compared between 90 HCV-infected patients [45 with HCV-induced cirrhosis and 45 with HCV-related hepatocellular carcinoma (HCC)] and 45 healthy Egyptian volunteers without any history of liver disease. Our results showed that at the TNF-α -308 position, the G/G allele was most common (78.5%) in the study population, with the G/A and A/A alleles occurring less frequently (13.3% and 8.1%, respectively). Frequencies of G/G, G/A, and A/A genotypes were 87%, 7%, and 6% in patients with liver cirrhosis and were 94%, 4%, and 2% in patients with HCC, respectively. Serum levels of TNF-α were significantly higher in HCV-infected patients than in healthy controls, indicating that the TNF-α -308 polymorphism does not influence the production of TNF-α. The serum level of TNF-α was positively correlated with HCV infection. Taken together, these findings suggest that the TNF-α -308 polymorphism may not be a host genetic factor associated with the severity of HCV infection, but may be an independent risk factor for HCC.

The Inflammatory Microenvironment in Hepatocellular Carcinoma: A Pivotal Role for Tumor-Associated Macrophages

“…Of note, TNF- α is also induced by NF- κ B in a positive feedback loop. TNF- α levels in HCC patients have also been investigated, but controversial data have been reported, whereas TNF- α (308) single nucleotide polymorphism was associated with cancer susceptibility [70]. …”

The tumor microenvironment in hepatocellular carcinoma (Review)

“…In a study by Kakumu et al TNF-αRs correlated with disease progression and IFN-α treatment did not affect their level (162). Regardin TNF-α polymorphism, the TNF-α (-308) SNP (single nucleotide polymorphisms) in the promoter region of the gene, which includes TNF-α1 (-308G) and TNF-α2 (-308A) alleles, is associated with cancer susceptibility and induced expression of TNF-α (153,(165)(166)(167).…”

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

“…Several reports have addressed possible implications of TNF‐α and IL‐10 promoter polymorphisms in HCV outcome; however, results have been inconsistent. Some studies have found significant correlation between the AA genotype of TNF‐α ‐308 and increased risk to cirrhosis or HCC [Yee et al, ; Dai et al, ; Jeng et al, , ; Feng et al, ; Radwan et al, ], on the other hand other studies failed to demonstrate significant association [Yu et al, ; Kusumoto et al, ; Dogra et al, ; Talaat et al, ; Corchado et al, ]. Regarding IL‐10, some studies indicated that patients with low IL‐10 production genotypes had a higher risk of liver cirrhosis and HCC [Bouzgarrou et al, , ], whereas other studies failed to confirm this association [Knapp et al, ; Abbott et al, ; Kusumoto et al, ; Paladino et al, ; Dogra et al, ; Ishida et al, ].…”