Smoking, folate and methylenetetrahydrofolate reductase status as interactive determinants of adenomatous and hyperplastic polyps of colorectum

Am J Med Genet. 2001 Jul 1;101(3):246-54. doi: 10.1002/ajmg.1370.


Most studies demonstrate increased risk of colorectal cancer (CRC) and adenomas in folate-deficient subjects or that high folate intake may afford some protection. Smoking increases such risk in some but not all studies. We investigated whether smoking, folate status and methylenetetrahydrofolate reductase (MTHFR) genotype predict the risk of adenomatous and hyperplastic polyps of colorectum. By colonoscopy, the type, number, size and extent of dysplasia of colorectal polyps were assessed in 443 subjects aged 63-72 years. We also determined RBC folate and the C667T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. Smoking, folate status and the C677T MTHFR polymorphism were strong, interactive determinants of high-risk adenomas (HRAs, defined as adenomas > or =10 mm in diameter, adenomas with villous components or with severe dysplasia). The risk was particularly high in smokers with low folate and the CT/TT genotype (risk category T) and in smokers with high folate and the CC genotype (risk category C). With non-smokers with low folate and the CC genotype as reference, the odds ratios (OR, 95% CI) were 8.7 (2.5-29.7) in category T and 9.9 (2.6-38.4) in category C. Notably, this risk pattern was also observed for hyperplastic polyps. In conclusion, in smokers, high folate status may confer increased or decreased risk for HRAs, depending on the MTHFR genotype. These data demonstrate the strong gene-nutrition interaction involving the C677T MTHFR polymorphism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyps / etiology
  • Adenomatous Polyps / genetics
  • Adenomatous Polyps / pathology*
  • Aged
  • Colorectal Neoplasms / etiology
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Cross-Sectional Studies
  • Female
  • Folic Acid / blood*
  • Gene Frequency
  • Genotype
  • Homocysteine / blood
  • Humans
  • Hyperplasia
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Middle Aged
  • Oxidoreductases Acting on CH-NH Group Donors / blood
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Risk Factors
  • Smoking / adverse effects*


  • Homocysteine
  • Folic Acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)