Genetic variability in the MTHFR gene and colorectal cancer risk using the colorectal cancer family registry

A. Joan Levine, Jane C. Figueiredo, Won Lee, Jenny N. Poynter, David Conti, David J. Duggan, Peter T. Campbell, Polly Newcomb, Maria Elena Martinez, John L. Hopper, Loic Le Marchand, John A. Baron, Paul J. Limburg, Cornelia M. Ulrich, Robert W. Haile

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Background: The MTHFR C677T TT genotype is associated with a 15% to 18% reduction in colorectal cancer risk, but it is not clear if other variants of the gene are associated with colorectal cancer risk. Methods: We used a tagSNP approach to comprehensively evaluate associations between variation in the MTHFR gene and colorectal cancer risk using a large family-based case-control study of 1,750 populationbased and 245 clinic-based families from the Colon Cancer Family Registry. We assessed 22 TagSNPs, selected based on pairwise r 2 >95%, using the Haploview Tagger and genotyped the TagSNPs on the Illumina GoldenGate or Sequenom platforms. The association between single nucleotide polymorphisms and colorectal cancer was assessed using log-additive, codominant, and recessive models. Results: From studying the population-based families, the C677T (rs1801133) and A1298C (rs1801131) polymorphisms were associated with a decreased colorectal cancer risk overall [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.63-1.04; and OR, 0.82; 95% CI, 0.64-1.07, respectively]. The 677 TT genotype was associated with a decreased risk of microsatellite-stable/microsatellite-low tumors (OR, 0.69; 95% CI, 0.49-0.97) and an increased risk of microsatellite-high tumors (OR, 2.22; 95% CI, 0.91-5.43; P interaction = 0.01), as well as an increased risk of proximal cancers and a decreased risk of distal and rectal cancers (P interaction = 0.02). No other single nucleotide polymorphism was associated with risk overall or within subgroups. Conclusion: The 677 TT and 1298 CC genotypes may each be associated with a decrease in colorectal cancer risk. We observed little evidence of additional genetic variability in the MTHFR gene relevant to colorectal cancer risk.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalCancer Epidemiology Biomarkers and Prevention
Issue number1
StatePublished - Jan 2010

ASJC Scopus subject areas

  • General Medicine


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