Several studies have indicated an association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and the risk of hepatocellular carcinoma (HCC). However, the conclusions are inconsistent. Therefore, a meta-analysis was performed.

Databases like Pubmed, EMBASE, and EBSCO (up to September 2012) were searched to retrieve case-control trials about MTHFR (C677T or A1298C) polymorphisms and HCC. Literatures were independently screened by two researchers according to the inclusion and exclusion criteria. Data were extracted and analyzed by software STATA 11.0.

Nine studies were included with 10 datasets and 5132 cases. C677T polymorphism was associated with HCC risk in a heterozygous model (TT vs. CT: OR=1.20, 95% CI: 1.02–1.40). For the A1298C polymorphism, a significantly decreased HCC risk was found in the dominant, heterozygous and homozygous models (CC vs. AA+AC: OR=0.52, 95% CI: 0.33–0.80; CC vs. AC: OR=0.50, 95% CI: 0.32–0.79; CC vs. AA: OR=0.52, 95% CI: 0.33–0.81). Subgroup analysis stratified by ethnicity and type of control further indicated decreased HCC risks in Asians (CC vs. AA+AC: OR=0.47, 95% CI: 0.26–0.84; CC vs. AC: OR=0.41, 95% CI: 0.24–0.71; CC vs. AA: OR=0.46, 95% CI: 0.27–0.78), studies with controls of healthy people (CC vs. AA: OR=0.54, 95% CI: 0.31–0.93; CC vs. AC: OR=0.54, 95% CI: 0.31–0.94; CC vs. AA+AC: OR=0.55, 95% CI: 0.32–0.94), and controls of non-HCC patients (CC vs. AC: OR=0.43, 95% CI: 0.19–0.96).

Homozygous carriers of MTHFR C677T mutation are more susceptible to HCC, but homozygous mutations of MTHFR A1298C may play a protective role for developing HCC.