One-carbon metabolism pathway and the risk of hepatocellular carcinoma in a Chinese population

Background. Imbalance of the one-carbon metabolic pathway may induce abnormal DNA synthesis and aberrant DNA methylation leading to liver carcinogenesis. Few studies have investigated the associations between promoter hypermethylation, micronutrients, and gene polymorphisms of the one-carbon metabolism pathway, in liver cancer. In this dissertation, the effects of plasma levels of folate, vitamin B12, and homocysteine (Hcy), single nucleotide polymorphisms (SNPs) of MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes, and APC, CDH1, P16INK4a, and MGMT promoter hypermethylations on HCC susceptibility in a Chinese population were studied. Methods. A population-based case-control study consisting of 204 incident liver cancer cases and 415 healthy population controls from Taixing, China was conducted in 2000. Plasma levels of folate and vitamin B12 were quantified by Quantaphase II radioassay and plasma levels of Hey were quantified by a competitive chemiluminescent enzyme immunoassay with the IMMULITE 2000 Automated Analyzer. Eight SNPs from the five genes were genotyped using either Taqman based assays, SNPlex, or PCR-RFLP. Gene promoter hypermethylations were measured using a fluorescence-based real-time Methylation Specific PCR (MSP) method. Unconditional logistic regression models were used to analyze potential associations with adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results. Higher plasma folate levels were inversely associated with liver cancer (p = 0.01) after the adjustment on potential confounding factors and plasma levels of vitamin B12 and Hcy. Plasma vitamin B12 levels have been found to be strongly associated with liver cancer (p<0.01). More than multiplicative interaction was suggested between low plasma folate levels and high plasma vitamin B12 levels on the odds of liver cancer (ORinteraction = 2.87, 95% CI: 1.02-8.09). MTHFR677 any T genotype was positively associated with HCC, with an OR of 1.64 (95% CI: 1.04-2.59) compared to individuals with the C/C genotype. In the stratified analysis, the association between MTHFR677 any T genotype and HCC was only observed among people with higher plasma levels of vitamin B12. MTR2756 any G and MTRR66 any G genotypes were inversely associated with HCC among non-alcohol drinkers. MTRR524 any T genotype was inversely associated with HCC among individuals with higher plasma Hcy levels. No obvious association was observed between peripheral blood DNA of APC or CDH1 promoter hypermethylation and HCC. Conclusion. Our results suggested that folate, vitamin B12, and genetic polymorphisms involved in the one-carbon metabolism pathway might play an important role in the development of liver cancer in Chinese population.