Association between single nucleotide polymorphisms (SNPs) of IL-6, TNF-alpha and VEGF-A genes, and susceptibility to hepatocellular carcinoma (HCC)

Abstract

Background: Many studies have demonstrated the association between SNPs and susceptibility to the development of diseases such as autoimmune diseases and neoplasms. These allelic variations may involve regulatory and coding regions of cytokine genes and may influence their transcriptional activity and, as a consequence, their protein levels. Hepatocarcinogenesis is a multi-step and multi-factorial process in which both environmental and genetic factors are involved. Liver cirrhosis (LC) of both HBV or HCV origin is considered the most important risk factors for HCC. Objectives: We evaluated the frequency of genetic polymorphisms of the cytokines IL-6 and TNFalpha and of VEGF-A in a group of patients with HCC(n=112) and underlying LC and compared them with a group of cirrhotic patients (n=90), without HCC, and a group of age- and sex-matched controls(n=124) in order to verify an eventual correlation between the allelic variations and the risk of developing tumor. Methods: DNA extracted from whole blood of the three Sicilian groups, was used for the evaluation of SNPs using Restriction Fragment Length Polymorphisms (RFLP) method in -174 position of IL-6 gene promoter (G/C transversion, G allele is associated with higher levels of the cytokine); -308 position of TNF-alpha gene promoter (G/A transition, G allele is associated with lower levels of the cytokine); 936 position of the coding region of VEGF-A gene (G/T transition, T allele is associated with high levels of VEGF-A). Data were analyzed was performed using the chi square and the Fisher exact tests were appropriated. P value was considered significant if <0.05. Results: Genotype frequency of IL-6 -174 was: controls vs HCC p < 0.79, controls vs cirrhosis p < 0.24, HCC vs controls p < 0.22; genotype frequency of TNF-alpha -308 was: controls vs HCC p < 0.057, controls vs cirrhosis p < 0.44, HCC vs controls p < 0.06; genotype frequency of VEGF-A 936 was: controls vs HCC p < 0.21, controls vs cirrhosis p < 0.22, HCC vs controls p < 0.60. Conclusion: These results do not demonstrate a significant correlation between the allelic variants considered and the risk of developing HCC. However the trend almost statistically significant of SNP -308 of TNF-alpha may suggest that in HCC subjects there are more A carriers with a higher susceptibility to the inflammatory type which may contribute to the development of the tumor.