Genetic variations in the one-carbon metabolism pathway genes and susceptibility to hepatocellular carcinoma risk: a case–control study

Abstract

Hepatocellular carcinoma (HCC) is the sixth common cancer and the third common cause of cancer mortality worldwide. However, the exact molecular mechanism of HCC remains uncertain. Many enzymes are involved in one-carbon metabolism (OCM), and single nucleotide polymorphisms (SNPs) in the corresponding genes may play a role in liver carcinogenesis. In this study, we enrolled 1500 HCC patients and 1500 cancer-free controls, which were frequency-matched by age, gender, and HBV infection status. Then eight SNPs from seven OCM genes (MTHFR, MTR, MTRR, FTHFD, GART, SHMT, and CBS) were evaluated. Results showed that six SNPs (MTHFR rs1801133, MTRR rs2287780, MTRR rs10380, FTHFD rs1127717, GART rs8971, and SHMT rs1979277) were significantly associated with HCC risk in Chinese population, with P values range from 2.26 × 10(-4) to 0.035). The most significant association was detected for GART rs8971. Compared with individuals with the TT genotype, the age- and sex-adjusted odds ratio (OR) for developing HCC was 1.44 (95% confidence interval (CI): 1.03-2.02) among those with the CC genotype and 1.30 (95% CI: 1.10-1.53) for those with CT genotype. Under the log-additive model, each additional copy of minor allele C was associated with a 1.28-fold increased risk of HCC (OR = 1.28, 95% CI: 1.12-1.45). These findings indicated that genetic variants in OCM genes might contribute to HCC susceptibility.

Response of MiRNA-22-3p and MiRNA-149-5p to Folate Deficiency and the Differential Regulation of MTHFR Expression in Normal and Cancerous Human Hepatocytes

“…The reversibility of methylation also suggests that this mechanism may be used as a treatment option in the future. Upon comparison of 1500 cases of HCC, 1500 healthy controls and individuals with the wild-type homozygous genotype, Zhang H et al[73]indicated that genetic variants in OCM genes (including MTHFR ) may contribute to HCC susceptibility, as those with the heterozygous genotype had a higher HCC risk. Qi YH et al[74]reported that homozygous carriers of the MTHFR C677T mutation are more susceptible to HCC, but homozygous mutations of MTHFR A1298C may play a protective role in the development of HCC.…”

Functional variants of the 5-methyltetrahydrofolate-homocysteine methyltransferase gene significantly increase susceptibility to prostate cancer: Results from an ethnic Han Chinese population

“…Soon afterwards, Gallegos-Arreola and colleagues reported that the 844ins68 polymorphism in the CBS gene contributes significantly to breast cancer susceptibility in Mexican population36. Nevertheless, negative results have been observed with regard to different types of cancer373839. Various factors, including differences in study design, study population and dietary assessment, could contribute to these inconsistent findings.…”

Genetic susceptibility of eight nonsynonymous polymorphisms in HLA-DRB1 gene to hepatocellular carcinoma in Han Chinese

“…Considering the fact that hepatocarcinogenesis is a multistep, multigenic process, and it is unlikely that the modulatory effect of any single variants would be dramatic in predicting cancer risk [29–31]. This opinion therefore inspires us to further interrogate the joint association of study polymorphisms in HLA-DRB1 gene with HCC risk.…”