Widely regarded as one of the most prevalent malignancies worldwide, gastric cancer (GC) is a common clinical condition of the digestive system. Reviewing 14 meta-analyses that evaluated the association between Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and GC risk, we observed inconsistent results, and the credibility of the significant correlation between the statistical results was ignored. With the aim of further exploring the association between MTHFRC677T and CA1298C and the risk of GC, we searched electronic databases, pooling 43 relevant studies and calculating odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for each of the five genetic models. Subgroup and regression analyses were performed to look for sources of heterogeneity and publication bias was assessed by funnel plots. To assess the plausibility of statistically significant associations, we used the FPRP test and the Venice criteria. Overall data analysis showed that MTHFRC677T polymorphism was significantly associated with GC risk, especially in Asians, while MTHFR CA1298C polymorphism was not associated with GC risk. However, in subgroup analysis by hospital-based controls, we found that MTHFR CA1298C might be a protective factor for GC. After credibility assessment, the statistical association between MTHFRC677T and GC susceptibility study was classified as "less credible positive result", while the result of MTHFR CA1298C was considered unreliable. In summary, this study strongly suggests that MTHFR, C677T and CA1298C polymorphisms are not significantly associated with the GC risk.

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