Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer

Pharmacogenetics. 2002 Jun;12(4):339-42. doi: 10.1097/00008571-200206000-00011.


A common polymorphism in a folate-metabolizing gene, methylenetetrahydrofolate reductase (MTHFR) 677C>T has been associated with reduced risk of colorectal cancer. In this study, we investigated whether a second common polymorphism of the gene, MTHFR 1298A>C, is an independent risk factor for colorectal cancer and if it is associated with plasma folate and total homocysteine (tHcy) levels. We also examined whether the 677C>T and 1298A>C polymorphisms are in linkage disequilibrium and whether combined heterozygosity confers additional (or reduced) risk of colorectal cancer. We conducted a nested case-control study of 211 incident colorectal cancer cases and 343 controls in the prospective Physicians' Health Study. The MTHFR 677C>T and 1298A>C polymorphisms were in linkage disequilibrium in this population. Compared to MTHFR 1298AA genotype, multivariate-adjusted relative risk of colorectal cancer was 0.73 (95% CI 0.37-1.43) for the MTHFR 1298CC genotype. The slight reduction in risk was not a result of its linkage disequilibrium with the 677C>T polymorphism. This polymorphism was not significantly correlated with the plasma folate and tHcy levels. The combined heterozygosity did not modify the cancer risk; nor did it change the plasma folate and tHcy significantly. We conclude that the MTHFR 1298A>C polymorphism is a less substantial independent risk factor for colorectal cancer compared to the 677C>T polymorphism.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Case-Control Studies
  • Colorectal Neoplasms / genetics*
  • Double-Blind Method
  • Folic Acid / blood*
  • Gene Frequency
  • Genotype
  • Humans
  • Incidence
  • Linkage Disequilibrium*
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Polymorphism, Genetic*
  • Prospective Studies
  • Surveys and Questionnaires


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