The development of HCC depends on some factors such as viral infection, environmental, behavioral, metabolism, and genetics [41, 42]. The contribution of SNP as a genetic factor is widely studied related to its role in the development of HCC, in which the prevalence of SNP is different in each population [5, 43, 44]. From the host factor, TNF-α is thought to play an important role in hepatocarcinogenesis through the induction of fibrogenic factors. Tumor Necrosis Factor-α is associated with increased necroinflammatory activity and liver fibrosis. Necroinflammation of hepatocytes triggers mutagenesis and activation of oncogens from protooncogenes in host cells, causing HCC .
Five biallelic SNPs in the promoter region Tumor Necrosis Factor-α gene were known: -1031T/C, -863C/A, -857C/T, -308G/A, and − 238G/A . There have been many studies conducted to determine the association between these five TNF-α SNPs and HCC risk. Several meta-analyses have also been performed to analyze the association between TNF-α SNP and HCC. However, to date, only few meta-analyses have analysed all these five SNPs with HCC risk. Hereby, we performed this updated meta-analysis to clarify the independent role of each of these five SNPs on HCC risk.
As research on SNP TNF-α -1031 T/C and HCC risk is still limited, we only found five studies investigating this SNP, even though many studies have shown significant association between this SNP with other diseases such as polycystic ovary syndrome and endometriosis [46, 47]. In a study conducted by Shin et al survival of HCC cases with TNF-α -1031 wild type (TT) genotype or SNP TC genotype was significantly better than those with the SNP CC genotype . However, in this meta-analysis, no significant relationship was found between the SNP and HCC risk in all genetic models. Meta-analysis conducted by Wei et al also shows that there is no significant relationship between this SNP and HCC risk .
This study shows a significant relationship between SNP TNF-α -863 C/A with HCC risk in allele models and dominant model analysis. A meta-analysis conducted by Wei et al also showed a significant relationship betweehis SNP and HCC in dominant and codominant (CA vs CC) model analysis . Polymorphism of TNF-α -863 C/A in the promoter region can influence TNF-α expression, however, the result is still conflicting. Some research suggest that it may increase TNF-α expression [49, 50], while other research show the opposite result in which it may decrease TNF-α expression [27, 51].
In the present study, we also found a significant relationship between SNP TNF-α-857 C/T with dominant model analysis. Limited studies were present regarding the relationship between this polymorphism with HCC risk, thus there were only 7 studies that came within our inclusion criteria. This is different from the meta-analysis conducted by Wei et al which showed no significant relationship between this SNP and HCC risk, however in that meta-analysis there were only 3 included studies .
There have been many previous studies investigating SNP TNF-α -308 G/A with HCC risk, thus we got 19 included studies. All five genetic analysis models showed a significant relationship between the SNP and HCC risk. This is in line with several previous meta-analysis studies, including those conducted by Hu et al and Tavakoulpour and Sali on allele models and dominant model analyses [16, 52], Wei et al on codominant dan dominant model analyses , and Xiao et al in all except recessive model analysis .
Studies on SNP TNF-α -238 G/A have also been extensively performed. Nevertheless, meta-analyses of these SNPs are still limited and yield conflicting results. The present study showed a significant relationship between this SNP and HCC risk. This is in line with a meta-analysis conducted by Xiao et al showing that this SNP is associated with HCC risk, although in that study only HBV-related HCC was studied . Another meta-analysis conducted by Hu et al, however, shows no significant relationship between this SNP with HCC risk in Asian population .
This meta-analysis still had several limitations. To date, there has rarely been any meta-analysis discussing the relationship between SNPs of TNF-α -1031 T/C, -863 C/A, -857 C/T, and − 238 G/A with HCC. Most present meta-analysis only focus on SNP − 308 G/A. We also got a small number of studies on SNPs − 1031 T/C, -863 C/A, -857 C/T, due to the limited number of studies. Research on these three SNPs, both observational and meta-analysis, is further needed in the future to find out the role of each of the three SNPs on HCC so that a stronger power of study will be obtained.
The second limitation of this study was that we only included studies in English language so that it does not rule out the exclusion of any good research in non-English languages. Third, HCC is a multifactorial process involving host, agent, and environment factors. The role of other host genomes, viruses, and the environment can influence the course and risk of HCC. Variations in genes adjacent to the TNF-α gene are said to also be able to regulate TNF-α expression . Epigenetic factors which include histone modification, non-coding RNA, and gene methylation can also affect TNF-α expression and contribute to HCC risk . Fourth, the study populations in our included studies came from various ethnicities (Asian, African, European and South American). Further research is required to determine the effects of these various TNF-α SNPs in each different population.