Genetic polymorphisms in themethylenetetrahydrofolate... : Hepatology (original) (raw)

Hepatobiliary Malignancies

Genetic polymorphisms in the methylenetetrahydrofolate reductase and thymidylate synthase genes and risk of hepatocellular carcinoma

Yuan, Jian-Min1*; Lu, Shelly C.2; Van Den Berg, David2; Govindarajan, Sugantha2; Zhang, Zhen-Quan3; Mato, Jose M.4; Yu, Mimi C.1

1 The Cancer Center, University of Minnesota, Minneapolis, Minnesota

2 Keck School of Medicine, University of Southern California, Los Angeles, California

3 Department of Epidemiology, Cancer Institute of Guangxi, Nanning, Guangxi, China

4 CIC bioGUNE, Ciberehd, Technology Park of Bizkaia, Derio, Bizkaia, Spain

* Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, 1300 South 2nd Street, Suite 300, Minneapolis, MN 55454

Email:[email protected]

Received 29 December 2006; Accepted 18 March 2007

Published online in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: United States National Institutes of Health; Grant Numbers: R35 CA53890 R01 CA80205 R01 CA43092 R01 CA98497 AA12677 AA13847 AT1576 DK51719; Grant sponsor: Spanish Ministry of Science; Grant Number: PN I+D SAF 2005-00855; Grant sponsor: CIBER from the Spanish Ministry of Health; Grant sponsor: European Union; Grant Number: HEPADIP EULSHM-CT-2005; Grant sponsor: Basque Department of Industry; Grant Number: ETORTEK 2005.

Potential conflict of interest: Nothing to report.

fax: 612-624-0315

Abstract

Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS) are known to play a role in DNA methylation, synthesis, and repair. The genetic mutations in MTHFR and TYMS genes may have influences on their respective enzyme activities. Data on the association studies of the MTHFR and TYMS genetic polymorphisms and risk of hepatocellular carcinoma (HCC) are sparse. MTHFR and TYMS genotypes were determined on 365 HCC cases and 457 healthy control subjects among Hispanic and non-Hispanic whites and African-Americans in Los Angeles County, California, and among Chinese in the city of Nanning, Guangxi, China. Relative to the high-activity genotype, each low-activity genotype of MTHFR was associated with a statistically nonsignificant 30% to 50% reduction in risk of HCC. Relative to the TYMS3′UTR +6/+6 genotype, individuals with 1 or 2 copies of the deletion allele had a statistically significant 50% reduction in risk of HCC. When we examined HCC risk by the total number of mutant alleles in the 3 polymorphic loci of MTHFR/TYMS (range, 0-4), there was a monotonic decrease in risk with increasing number of mutant alleles ( P for trend = 0.003). Individuals possessing the maximum number of mutant alleles ( i.e., 4) had an odds ratio of 0.46 (95% confidence interval = 0.23-0.93) for HCC compared with those with no or only 1 mutant allele. Conclusion: This study supports the hypothesis that reduced MTHFR activity and enhanced TYMS activity, both of which are essential elements in minimizing uracil misincorporation into DNA, may protect against the development of HCC. (Hepatology 2007.)

Abbreviations: 2R, double repeat; 3R, triple repeat; bp, base pair; dTMP, deoxythimidine monophosphate; dUTP, deoxyuridine monophosphate; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatits C virus; MTHFR, methylenetetrahydrofolate reductase; SAMe, S-adenosylmethionine; TYMS, thymidylate synthase; TYMSER, enhancer region of the TYMS gene.