title: Methionine synthase and thymidylate synthase gene polymorphisms and colorectal adenoma risk: the self defense forces study.
abstract: Folate-mediated one-carbon metabolism has been implicated in colorectal carcinogenesis. We investigated associations of functional genetic polymorphisms of methionine synthase (MTR), MTR reductase (MTRR), and thymidylate synthase (TS) with colorectal adenomas. The study subjects were 455 cases of colorectal adenomas and 1052 controls with no polyp at colonoscopy. Genotypes were determined for MTR A2756G, MTRR A66G and two polymorphisms in the TS gene, 28-bp tandem repeat polymorphism in the promoter enhancer region (TSER) and 6-bp deletion polymorphism at position 1494 in the 3' untranslated region (TS 1494del6). We also examined the alcohol-genotype and gene-gene interactions on adenoma risk. The GG genotype of MTR A2756G was associated with an increased risk of colorectal adenomas; odds ratios for AG and GG versus AA genotype were 0.99 (95% confidence interval 0.78-1.26) and 1.72 (1.04-2.82), respectively. The increase in the risk associated with MTR 2756GG genotype was evident in men with high alcohol consumption (≥30 mL/d), but not in those with low alcohol consumption (interaction P = 0.03). Men who were homozygous for the TSER double-repeat allele had a slightly decreased risk of colorectal adenomas as compared with those homozygous for the TSER triple-repeat allele. Neither MTRR A66G nor TS 1494del6 was associated with colorectal adenomas. There was no measurable interaction either between MTR A2756G and MTRR A66G or between TSER and TS 1494del6. MTR A2756G appears to be associated with colorectal adenoma risk differently according to alcohol consumption. The MTR-catalyzed reaction may play an important role in the development of colorectal adenomas.
authors.affiliation: Department of Preventive Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yoshimitsu
authors.forename: Makiko
authors.initials: M
authors.lastname: Morita
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Hamachi
authors.forename: Shinji
authors.initials: S
authors.lastname: Tabata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.forename: Osamu
authors.initials: O
authors.lastname: Tajima
authors.forename: Kousaku
authors.initials: K
authors.lastname: Uezono
authors.forename: Keizo
authors.initials: K
authors.lastname: Ohnaka
authors.forename: Suminori
authors.initials: S
authors.lastname: Kono
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000236:Adenoma / Q000235:genetics*; D000328:Adult; D000428:Alcohol Drinking / Q000453:epidemiology; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D004843:Epistasis, Genetic; D005287:Ferredoxin-NADP Reductase / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D011110:Polymorphism, Genetic; D020080:Tandem Repeat Sequences; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; D013940:Thymidylate Synthase