Genetic variants in folate metabolism-related genes, serum folate and hepatocellular carcinoma survival: the Guangdong Liver Cancer Cohort study

Folate metabolism is involved in the development and progression of various cancers. We investigated the association of single nucleotide polymorphisms (SNP) in folate-metabolising genes and their interactions with serum folate concentrations with overall survival (OS) and liver cancer-specific survival (LCSS) of newly diagnosed hepatocellular carcinoma (HCC) patients. We detected the genotypes of six SNP in three genes related to folate metabolism: methylenetetrahydrofolate reductase (<i>MTHFR</i>), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (<i>MTRR</i>) and 5-methyltetrahydrofolate-homocysteine methyltransferase (<i>MTR</i>). Cox proportional hazard models were used to calculate multivariable-adjusted hazard ratios (HR) and 95 % CI. This analysis included 970 HCC patients with genotypes of six SNP, and 864 of them had serum folate measurements. During a median follow-up of 722 d, 393 deaths occurred, with 360 attributed to HCC. In the fully-adjusted models, the <i>MTRR</i> rs1801394 polymorphism was significantly associated with OS in additive (per <i>G</i> allele: HR = 0·84, 95 % CI: 0·71, 0·99), co-dominant (AG <i>v</i>. AA: HR = 0·77; 95 % CI: 0·62, 0·96) and dominant (AG + GG <i>v</i>. AA: HR = 0·78; 95 % CI: 0·63, 0·96) models. Carrying increasing numbers of protective alleles was linked to better LCSS (HR_{10–12 <i>v</i>}. _2–6 = 0·70; 95 % CI: 0·49, 1·00) and OS (HR_{10–12 <i>v</i>}. _2–6 = 0·67; 95 % CI: 0·47, 0·95). Furthermore, we observed significant interactions on both multiplicative and additive scales between serum folate levels and <i>MTRR</i> rs1801394 polymorphism. Carrying the variant G allele of the <i>MTRR</i> rs1801394 is associated with better HCC prognosis and may enhance the favourable association between higher serum folate levels and improved survival among HCC patients.