title: One-carbon metabolism-related gene polymorphisms and risk of breast cancer.
abstract: Environmental exposures and/or genetic background in Japanese population, which might contribute to the relatively low breast cancer incidence rates in Japan, have not been clarified in detail. Folate plays an essential role in DNA methylation and synthesis, and thus may be involved in the development of breast cancer. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T), methionine synthase (MTR A2756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase (TS), influence folate metabolism, but epidemiological studies have yielded inconsistent findings. We therefore conducted a case-control study to clarify their associations with breast cancer risk. A total of 456 breast cancer cases and 912 age-matched and menopausal status-matched non-cancer controls were genotyped for the polymorphisms. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic models adjusted for potential confounders and gene-environment interactions between the polymorphisms and folate consumption were also evaluated. We observed an increased risk of postmenopausal breast cancer with the MTHFR 677TT genotype (OR = 1.83, 95% CI: 1.08-3.11) with a menopausal status-based analysis. In combination analysis, a significantly elevated OR was found among postmenopausal women with the MTHFR 677TT genotype and lower intake of dietary folate compared with those with 677CC genotype and adequate folate consumption (OR = 2.80, 95% CI: 1.11-7.07). In addition, interaction between the MTRR A66G polymorphism and folate intake for risk of postmenopausal breast cancer was observed (interaction P = 0.008). Our findings indicated that the MTHFR and MTRR polymorphisms were associated with individual susceptibility to breast cancer among postmenopausal women.
authors.affiliation: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. suzuki@aichi-cc.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hirose
authors.forename: Akio
authors.initials: A
authors.lastname: Hiraki
authors.forename: Takakazu
authors.initials: T
authors.lastname: Kawase
authors.forename: Miki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Toshinari
authors.initials: T
authors.lastname: Yamashita
authors.forename: Hiroji
authors.initials: H
authors.lastname: Iwata
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tajima
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005492:Folic Acid / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007564:Japan; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013940:Thymidylate Synthase / Q000235:genetics
chemical_list: D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D013940:Thymidylate Synthase