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Associations between Two Common Variants C677T and A1298C in the Methylenetetrahydrofolate Reductase Gene and Measures of Folate Metabolism and DNA Stability (Strand Breaks, Misincorporated Uracil, and DNA Methylation Status) in Human Lymphocytes In vivo

¹ Division of Cellular Integrity, Rowett Research Institute, Aberdeen, United Kingdom; ² Epidemiology Group, Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom; ³ Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama; and ⁴ Centre for Human Nutrition, University of Sheffield, Sheffield, United Kingdom

Requests for reprints: Susan J. Duthie, Division of Cellular Integrity, Rowett Research Institute, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, United Kingdom. Phone: 44-1224-712751, ext. 2324; Fax: 44-1224-716629. E-mail: sd{at}rri.sari.ac.uk

Objective: Homozygosity for variants of the methylenetetrahydrofolate reductase (MTHFR) gene is associated with decreased risk for colorectal cancer. We have investigated the relationships between two variants of the MTHFR gene (C677T and A1298C) and blood folate, homocysteine, and genomic stability (strand breakage, misincorporated uracil, and global cytosine methylation in lymphocytes) in a study of 199 subjects. Results: The frequencies of homozygosity for the C677T and A1298C variants of the MTHFR gene were 12.6% and 14.6%, respectively. Plasma homocysteine, folate, vitamin B₁₂, 5-methyltetrahydrofolate, and RBC folate were determined in the C677T genotypes. Plasma folate was significantly lower (P < 0.001) in the homozygous variants (6.7 ± 0.6 ng/mL) compared with wild-types (8.8 ± 0.4 ng/mL) and heterozygotes (9.1 ± 0.5 ng/mL). Homocysteine was significantly higher (P < 0.05) in homozygous variants (13.2 ± 1.1 µmol/L) compared with homozygous subjects (10.9 ± 0.4 µmol/L). Homozygous variants had significantly lower (P < 0.05) RBC folate (84.7 ± 6.3 ng/mL) compared with wild-types (112.2 ± 5.2 ng/mL) and heterozygous individuals (125.1 ± 6.6 ng/mL). No significant difference in RBC folate was observed between wild-types and heterozygotes. The A1298C variant did not influence plasma homocysteine, folate, 5-methyltetrahydrofolate, vitamin B₁₂, or RBC folate. Lymphocyte DNA stability biomarkers (strand breaks, misincorporated uracil, and global DNA methylation) were similar for all MTHFR C677T or A1298C variants. Conclusion: Data from this study do not support the hypothesis that polymorphisms in the MTHFR gene increase DNA stability by sequestering 5,10-methylenetetrahydrofolate for thymidine synthesis and reducing uracil misincorporation into DNA.

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