MTHFR Polymorphisms, Dietary Folate Intake, and Breast Cancer Risk

Abstract

Folate plays an important role in DNA methylation, synthesis, and repair; intake has been associated with breast cancer. The folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR) is polymorphic at nucleotides 677 (C3 T) and 1298 (A3 C), resulting in allozymes with decreased activity. We evaluated these two common polymorphisms and their effects on the folate intake and breast cancer risk association in a population-based case-control study of 1144 breast cancer cases and 1236 controls using a PCR-RFLP-based assay. All subjects completed in-person interviews, which included a food frequency questionnaire. Unconditional logistic regression models were used to calculate odds ratios and their 95% confidence intervals, after adjusting for potential confounding factors. Cases and controls were similar in the distribution of MTHFR polymorphisms at codons 677 (41.4% cases and 41.8% controls carried the T allele) and 1298 (17.6% cases and 17.5% controls carried the C allele). An inverse association of breast cancer risk with folate intake was observed in all genotype groups, particularly among subjects with the 677TT genotype. Compared with those with the 677CC genotype and high folate, the adjusted odds ratios (95% confidence intervals) associated with low folate intake were 1.94 (1.15-3.26), 2.17 (1.34 -3.51), and 2.51 (1.37-4.60) for subjects who had CC, CT, and TT genotypes (p for interaction, 0.05). No modifying effect of A1298C genotypes on the association of folate intake with breast cancer risk was observed. Results of this study suggest that the MTHFR C677T polymorphisms may modify the association between dietary folate intake and breast cancer risk.

Genetic polymorphisms in the one‐carbon metabolism pathway and breast cancer risk: A population‐based case–control study and meta‐analyses

“…Similarly, a meta-analysis including data from our study and 12 previously published studies 5,6,8,9,13,14,27,28 showed no evidence for an overall association for MTHFR E429A (summary OR 5 1.00; 95% CI 0.85-1.17 based on 6,521 cases and 8,515 controls; Table III). Results were similar across racial groups and geographical regions.…”

“…A meta-analysis including data from this study and 21 previously published studies [5][6][7][8][9][10][11][12][13][14][27][28][29][30][31][32][33] showed no association between variant vs. common homozygote genotypes for MTHFR A222V and breast cancer risk [summary OR (95% CI) 5 0.99 (0.86-1.15), based on 8,330 cases and 10,825 controls]. Similarly, a meta-analysis including data from our study and 12 previously published studies 5,6,8,9,13,14,27,28 showed no evidence for an overall association for MTHFR E429A (summary OR 5 1.00; 95% CI 0.85-1.17 based on 6,521 cases and 8,515 controls; Table III).…”

“…15 Studies have also suggested an interaction between folate and variants of MTHFR. 5,6,8,13 Variation in other genes in the one-carbon metabolism pathway could affect breast cancer risk, but have not been evaluated in published studies. Methionine synthase (MTR) catalyzes the remethylation of homocysteine to methionine and is essential for maintaining adequate intercellular folate pools.…”

“…Most epidemiological studies of breast cancer have focused on 2 putative functional polymorphisms in the methylenetetrahydrofolate gene (MTHFR A222V and E429A) involved in the conversion of N 5 ,N 10 -methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major circulating form of folate; however, findings are inconclusive. [5][6][7][8][9][10][11][12][13][14] A recently published meta-analysis of studies showed no evidence for an association between MTHFR A222V and breast cancer risk in postmenopausal women; however, it suggested an association in premenopausal women. 15 Studies have also suggested an interaction between folate and variants of MTHFR.…”

The thermolabile variant of MTHFR is associated with depression in the British Women's Heart and Health Study and a meta-analysis

“…Further, there is substantial error in the measurement of folate, and intake at a particular time point may not be a good indicator of average lifetime exposure to folate. In two studies of breast cancer and folate intake, the intraclass correlation coefficient for folate intake measured on two occasions was 0.36, 28 and for folate measured by food frequency questionnaire compared with 24 h recall was 0.26. 29 There are promising results from small preliminary randomized controlled trials of folate supplementation and depression.…”