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.
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