Infection by HPV is not exclusive to cause cervical cancer. Genetic polymorphism is also important in inducing cervicogenesis collectively. Moreover, in distinct populations, the relationship between the risk of cervical tumorigenesis and gene polymorphism was almost various. In our analysis, 1145 cases and 1690 controls from nine publications were involved. The meta-analysis results showed that MTHFR A1298C is a risk factor for cervical cancer, especially in Asian population. As to MTHFR A1298C polymorphism, in previous study, Zhuo et al.  published the first meta-analysis assess the association between MTHFR A1298C gene polymorphisms and cervical cancer risk and did not find significant associations. In contrast, recent meta-analysis by Yi et al. , including five studies, suggested that the significant associations between MTHFR A1298C polymorphism and cervical cancer were found among Asians. However, these studies were limited to small sample sizes and high heterogeneity. Therefore, we performed a comprehensive large-scale meta-analysis to investigate these associations. We performed a more comprehensive large-scale meta-analysis (nine studies involving 2835 individuals) to accurately assess these associations.
Folate was indicated a protective effect on cervical epithelial cell . In addition, multiple clinical evidences have reported that evaluated level folate level was inversely related with the risk of cervical cancer [19, 25, 26]. As the introduction described, folate metabolism is very important for protection of cervical epithelial cell through maintain the methylation, repair, and synthesis of DNA . In physically, folates appear to be essential for cell growth and cell cycle. Once folate deficiency induces lower proliferation rates by increased apoptosis and cell cycle arrest. Thus, this is very negative for normal cell survival, which would promote cell transformation into cancer cells. Some study has shown that low level of serum folate may increase the risk of cervical cancer. Furthermore, it could be potential synergy with HPV infection, promoting cervical cancer development . In our study, we set up the relation of MTHFR, as a key enzyme involving the chemical reaction of vitamin folate, A1298C polymorphism and cervical cancer susceptibility. It is this polymorphism that affects the activity of the enzyme and leads to low folate concentration in serum. To be more specific, the activity was decreased when a substitution of glutamate with alanine occurred.
In basic research, carriers of variant alleles for MTHFR1298 exhibit genome-wide DNA hypomethylation, which is a characteristic of genome instability . When the activity of MTHFR was decreased or lose, it would lead to relaxation of heterochromatin, a decrease of H3K9me3 levels that often associates with heterochromatin at the centromeric and telomeric regions, and an increase of certain transcripts at the centromeric region. In summary, it would destroy heterochromatin or whole genome stability . Thus, it was not hard to speculate the hazardous of MTHFR A1298C. It has reported that the MTHFR 1298C allele frequency is approximately 20- 70% in Asia, 24-46% in Europe, and 0-15% in America , which may explain why Asians are strong association. This could give us an appropriate reminder that Asians with carriers of variant alleles for MTHFR1298 may probably more likely to get cervical cancer, if they are infected HPV simultaneously.
In our study, there are still some limitations as follows. Firstly, the sample size was relatively small and may not have provided sufficient statistical power. More studies with a larger sample size are required. Meanwhile, it is hoped that the exploration was expanded on the association of MTHFR A1298C polymorphism and tumors of the female reproductive system, including ovarian cancer, which will make the study more broad-spectrum and meaningful. Secondly, the subgroup analyses according to age, histological types and other elements were not performed owing to insufficient relevant data. Thus, it is suggested that future study could combine environmental factors, age and genetic polymorphism together to explore the interaction. Thirdly, given that the MTHFR has two types of polymorphisms, whether there is an interaction is unknown.