Journal Article

One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan

Keitaro Matsuo, Hidemi Ito, Kenji Wakai, Kaoru Hirose, Toshiko Saito, Takeshi Suzuki, Tomoyuki Kato, Takashi Hirai, Yukihide Kanemitsu, Hiroshi Hamajima and Kazuo Tajima

in Carcinogenesis

Volume 26, issue 12, pages 2164-2171
Published in print December 2005 | ISSN: 0143-3334
Published online July 2005 | e-ISSN: 1460-2180 | DOI:
One-carbon metabolism related gene polymorphisms interact with alcohol drinking to influence the risk of colorectal cancer in Japan

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  • Clinical Cytogenetics and Molecular Genetics


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One-carbon metabolism, in which folate plays an essential role, is involved in DNA methylation and synthesis, and is suspected of impacting on colorectal carcinogenesis. Alcohol is well recognized as a risk factor for colorectal cancer (CRC) and interactions with one-carbon metabolism have also been suggested. Therefore, functional polymorphisms in genes encoding members of this pathway, MTHFR C677T and A1298C (genes for methylenetetrahydrofolate reductase), MTR A2756G (gene for methionine synthase) and TS (gene for thymidylate synthase) tandem repeats polymorphisms, have attracted attention. We conducted a matched case–control study with 257 incident CRC cases and 771 non-cancer controls at the Aichi Cancer Center to clarify associations among folate intake and four polymorphisms with reference to CRC risk. Gene–environment interaction between polymorphisms, drinking and folate consumption was also evaluated. None of the polymorphisms showed any significant impact on CRC risk by genotype alone, but when combined with alcohol consumption the MTHFR 677CC type showed a significantly reduced risk (odds ratio (OR) = 0.45, 95% confidence interval (CI): 0.23–0.86) (P = 0.01). MTR GG showed increased risk only among drinkers (OR = 3.35, 1.40–8.05) (P = 0.047). TS polymorphism did not show statistical significance by genotype alone, while interaction with drinking was significant (P = 0.028). The association was not changed even after stratification by daily folate consumption and drinking habit. In conclusion, we found consistently significant interactions between one-carbon metabolism-related polymorphisms and alcohol drinking.

Keywords: ACCH, Aichi Cancer Center Hospital; BMI, body-mass index; CRC, colorectal cancer; FVO, first visit outpatients; HWE, Hardy–Weinberg equilibrium; HERPACC, Hospital-based Epidemiologic Research Program at Aichi Cancer Center; MS, methionine synthase; MTHFR, methylenetetrahydrofolate reductase; PY, pack-year; PCR, polymerase chain reaction; PCR-RFLP, PCR-restriction-fragment-length polymorphism; SQFFQ, semi-quantitative food frequency questionnaire; TS, thymidylate synthase; 2R, two repeats allele; VNTR, variable number of tandem repeat

Journal Article.  5405 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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