LINE-1 Methylation in Chronic HBV Infected Patients: Association with HCC, Gender and MTHFR C677T Polymorphism.

Background: Polymorphism of methylene tetrahydrofolate reductase (MTHFR) C677T has been reported to be associated with HBV-related hepatocellular carcinoma (HCC) risk. However, the underlying mechanism remains elusive. DNA methylation has been suggested to be associated with HCC onset. MTHFR is the key enzyme in folic acid metabolism, thus, it influences the production of the main donor of methyl groups for DNA methylation. This study aimed to determine the association of global DNA methylation with MTHFR C677T polymorphism in chronic HBV infected patients, as well as its association with HCC and gender. Methods: In all, 130 chronic hepatitis B (CHB) and 131 HBV-related HCC patients were enrolled in the study. The methylation level of long interspersed nuclear element-1 (LINE-1), the surrogate marker of global DNA methylation, and MTHFR C677T genotypes were determined. Results: The HCC group showed significantly lower LINE-1 methylation than the CHB group (p = 0.016). Females were observed to have a markedly lower LINE-1 methylation level than males in both CHB and HCC groups (p = 0.000, p = 0.014, respectively). A significant relationship between MTHFR C677T polymorphism and LINE-1 methylation was observed in the CHB group (F = 5.985, p = 0.003). CT, TT, and CT + TT genotypes were significantly associated with lower LINE-1 methylation level compared with the CC genotype (p = 0.005, p = 0.018, p = 0.001, respectively). In addition, the association between MTHFR C677T and LINE-1 methylation was more significant in females (F= 5.036, p = 0.011) than in males (F = 3.083, p = 0.051); further, the association was significant in the subjects older than 60 years (F = 3.865, p = 0.028), but not in the subgroup aged less than 60 years (F = 2.496, p = 0.089). Conclusions: LINE-1 methylation level in chronic HBV infected patients was associated with the occurrence of HBV-related HCC, gender, and MTHFR C677T polymorphism.