Gastroenterology

Gastroenterology

Volume 131, Issue 6, December 2006, Pages 1706-1716
Gastroenterology

Clinical–alimentary tract
Dietary Factors and Biomarkers Involved in the Methylenetetrahydrofolate Reductase Genotype–Colorectal Adenoma Pathway

https://doi.org/10.1053/j.gastro.2006.09.010Get rights and content

Background & Aims: Methylenetetrahydrofolate reductase (MTHFR) is involved in intracellular folate homeostasis and metabolism. We assessed 2 polymorphisms in the MTHFR gene (C677T and A1298C) in relation to colorectal adenoma recurrence and conducted analyses to investigate their joint effects with plasma and dietary markers of folate status. Methods: We prospectively analyzed data from 1598 individuals genotyped for the C677T polymorphism and 1583 with data on A1298C. Results: Among nonusers of multivitamin supplements, compared with wild-type carriage, higher odds of recurrence were observed for those with the 677 TT variant (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.04–2.63) and a nonsignificant increase was observed among those with the 1298 CC variant (OR, 1.50; 95% CI, 0.93–2.40). Diplotype analyses among nonusers of multivitamins showed that individuals who carry the MTHFR 677TT_1298AA or 677CC_1298CC combination were significantly more likely to have a recurrence compared with those with the double wild-type (OR, 2.05 for TT_AA and 1.85 for CC_CC). Higher odds of recurrence were observed among participants with low folate intake or plasma folate and the 677 TT or 1298 CC variants compared with those with lower levels and the wild-type or heterozygous genotypes. Stronger associations were shown for the combination of high homocysteine and the 677 TT variant (OR, 2.29; 95% CI, 1.00–5.26) but not the 1298 CC variant (OR, 1.09; 95% CI, 0.39–3.01). Conclusions: We propose that the effect of the MTHFR genotypes on increasing risk of adenoma recurrence in the presence of a low folate status is through their increase in homocysteine concentrations, which in turn could result in DNA hypomethylation via pathways involving S-adenosylhomocysteine.

Section snippets

Study Populations

Analyses were conducted in participants from the Wheat Bran Fiber and the Ursodeoxycholic Acid trials, the details of which have been reported elsewhere.35, 36, 37 A brief description of each study is provided later. The studies were approved by the University of Arizona Human Subjects Committee and the Institutional Review Board.

The Wheat Bran Fiber trial was a double-blind controlled trial conducted to compare the effect of a high-fiber vs a low-fiber cereal supplement on adenoma recurrence

Results

Among the 1598 individuals genotyped for MTHFR C677T, the prevalence of the T allele was 32.9%; 45.8% were CC homozygotes, 42.7% were heterozygotes, and the remaining 11.5% were TT homozygotes. The corresponding values for the 1583 individuals with MTHFR A1298C data were as follows: 47.3% AA homozygotes, 42.4% heterozygotes, and 10.3% CC homozygotes, with a C allele prevalence of 31.5%. No significant difference in regard to risk factors of interest was observed between this subset of

Discussion

The availability of methyl groups for DNA methylation reactions is regulated primarily by the activity of MTHFR through its role in 1-carbon metabolism. The totality of the published data on the association of MTHFR C677T polymorphism and colorectal cancer indicate that individuals with the TT variant are at lower risk of developing colorectal cancer12; however, the opposite has been shown for other gastrointestinal cancers.48, 49, 50, 51, 52, 53 As well, the carriage of the 677 TT genotype

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  • Cited by (0)

    Supported by Public Health Service grants CA-41108 and CA-23074, the Specialized Program of Research Excellence in Gastrointestinal Cancer (CA-95060) from the National Cancer Institute, and a Cancer Research and Prevention Foundation grant.

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