Colorectal cancer and the methylenetetrahydrofolate reductase 677C -> T and methionine synthase 2756A -> G polymorphisms: a study of 2,168 case-control pairs from the JANUS cohort.
Polymorphisms in genes involved in the metabolism of folate and methyl groups have been implicated with risk of colorectal cancer. We evaluated the relation between the polymorphisms 677C --> T of the methylenetetrahydrofolate reductase (MTHFR) and 2756A --> G of the methionine synthase (MTR) genes and risk of colorectal cancer. From the Norwegian JANUS cohort of 309,000 subjects, 2,179 cases were identified and a similar number of controls were selected. The controls were matched for age, gender, time, and place of serum donation. Genotypes were obtained from 2,168 case-control pairs by real-time PCR of serum samples. Risk of colorectal cancer was estimated with conditional and unconditional logistic regression. Median age at diagnosis was 60 years and mean follow-up 13 years. The odds ratio for MTHFR TT versus CC was 0.73 [95% confidence interval (95% CI), 0.58-0.92] and for MTR GG versus AA was 0.65 (95% CI, 0.47-0.90). No interaction between the polymorphisms was found. Relative risk estimates were similar for men and women, and for young and old age at diagnosis. For the MTR GG genotype, risk reduction was observed at the two most distal sites (sigmoideum and rectum) only (P = 0.003). The folate marker, serum total homocysteine (tHcy), was measured in 1,837 subjects. Odds ratio for the upper versus the lower tertile of tHcy was 1.32 (95% CI, 1.04-1.68). No significant effect modification by tHcy levels was detected for either polymorphism. In summary, we found significantly reduced risk of colorectal cancer in subjects with the MTHFR 677 TT and MTR 2756 GG genotypes. No interaction between the polymorphisms, or of either polymorphism with tHcy, was detected.
Ulvik
Arve
A
Department of Pharmacology, University of Bergen, Armauer Hansens hus, N-5021 Bergen, Bergen, Norway. arve.ulvik@farm.uib.no
Vollset
Stein Emil
SE
Hansen
Svein
S
Gislefoss
Randi
R
Jellum
Egil
E
Ueland
Per Magne
PM
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D009664:Norway / Q000453:epidemiology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors
D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase