Article

MTHFR 677C -> T genotype is associated with folate and homocysteine concentrations in a large, population-based, double-blind trial of folic acid supplementation

National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA.
American Journal of Clinical Nutrition (Impact Factor: 6.92). 06/2011; 93(6):1365-72. DOI: 10.3945/ajcn.110.004671
Source: PubMed

ABSTRACT The methylenetetrahydrofolate reductase (MTHFR) genotype is associated with modification of disease and risk of neural tube defects. Plasma and red blood cell (RBC) folate and plasma homocysteine concentrations change in response to daily intakes of folic acid supplements, but no large-scale or population-based randomized trials have examined whether the MTHFR genotype modifies the observed response.
We sought to determine whether the MTHFR 677C→T genotype modifies the response to folic acid supplementation during and 3 mo after discontinuation of supplementation.
Northern Chinese women of childbearing age were enrolled in a 6-mo supplementation trial of different folic acid doses: 100, 400, and 4000 μg/d and 4000 μg/wk. Plasma and RBC folate and plasma homocysteine concentrations were measured at baseline; after 1, 3, and 6 mo of supplementation; and 3 mo after discontinuation of supplementation. MTHFR genotyping was performed to identify a C→T mutation at position 677 (n = 932).
Plasma and RBC folate and homocysteine concentrations were associated with MTHFR genotype throughout the supplementation trial, regardless of folic acid dose. MTHFR TT was associated with lower folate concentrations, and the trend of TT < CC was maintained at even the highest doses. Folic acid doses of 100 μg/d or 4000 μg/wk did not reduce high homocysteine concentrations in those with the MTHFR TT genotype.
MTHFR genotype was an independent predictor of plasma and RBC folate and plasma homocysteine concentrations and did not have a significant interaction with folic acid dose during supplementation. This trial was registered at clinicaltrials.gov as NCT00207558.

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    • "Both a previous dose-finding trial [10] and a dose-response trial [11] have discussed the relationship between homocysteine-lowering efficacy and optimal dose of FA supplementation, but without considering the possible modifying effect of MTHFR C677T polymorphism. A more recent study [12] evaluated the effect of MTHFR C677T polymorphism on the response to different doses of FA supplementation (0.1 mg/d, 0.4 mg/d, 4 mg/d and 4 mg/week) in northern Chinese women of childbearing age and reported that the MTHFR 677 TT genotype was an independent predictor of plasma homocysteine concentrations, irrespective of FA dose, which was consistent with our results. However, the study population consisted of young women and the FA dosage category was not optimal, being either too low (0.1 mg/d) or too high (4 mg/d). "
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    ABSTRACT: This study aimed to investigate if the homocysteine-lowering efficacy of two commonly used physiological doses (0.4 mg/d and 0.8 mg/d) of folic acid (FA) can be modified by individual methylenetetrahydrofolate reductase (MTHFR) C677T and/or methionine synthase (MTR) A2756G polymorphisms in hypertensive Chinese adults. A total of 480 subjects with mild or moderate essential hypertension were randomly assigned to three treatment groups: 1) enalapril only (10 mg, control group); 2) enalapril-FA tablet [10:0.4 mg (10 mg enalapril combined with 0.4 mg of FA), low FA group]; and 3) enalapril-FA tablet (10:0.8 mg, high FA group), once daily for 8 weeks. After 4 or 8 weeks of treatment, homocysteine concentrations were reduced across all genotypes and FA dosage groups, except in subjects with MTR 2756AG /GG genotype in the low FA group at week 4. However, compared to subjects with MTHFR 677CC genotype, homocysteine concentrations remained higher in subjects with CT or TT genotype in the low FA group (P < 0.05 for either of these genotypes) and TT genotype in the high FA group (P < 0.05). Furthermore, subjects with TT genotype showed a greater homocysteine-lowering response than did subjects with CC genotype in the high FA group (mean percent reduction of homocysteine at week 8: CC 10.8% vs. TT: 22.0%, P = 0.005), but not in the low FA group (CC 9.9% vs. TT 11.2%, P = 0.989). This study demonstrated that MTHFR C677T polymorphism can not only affect homocysteine concentration at baseline and post-FA treatment, but also can modify therapeutic responses to various dosages of FA supplementation.
    Nutrition Journal 10/2012; 11:2. DOI:10.1186/1475-2891-11-2 · 2.64 Impact Factor
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    • "Detailed analysis of the plasma and RBC folate and homocysteine response and response by MTHFR genotype are published elsewhere [7], [8]. The effects of folic acid supplementation and withdrawal on folate and homocysteine concentrations for the stratified random sample use in this study are presented in Table 1. "
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    ABSTRACT: Folate is a source of one-carbons necessary for DNA methylation, a critical epigenetic modification necessary for genomic structure and function. The use of supplemental folic acid is widespread however; the potential influence on DNA methylation is unclear. We measured global DNA methylation using DNA extracted from samples from a population-based, double-blind randomized trial of folic acid supplementation (100, 400, 4000 µg per day) taken for 6 months; including a 3 month post-supplementation sample. We observed no changes in global DNA methylation in response to up to 4,000 µg/day for 6 months supplementation in DNA extracted from uncoagulated blood (approximates circulating blood). However, when DNA methylation was determined in coagulated samples from the same individuals at the same time, significant time, dose, and MTHFR genotype-dependent changes were observed. The baseline level of DNA methylation was the same for uncoagulated and coagulated samples; marked differences between sample types were observed only after intervention. In DNA from coagulated blood, DNA methylation decreased (-14%; P<0.001) after 1 month of supplementation and 3 months after supplement withdrawal, methylation decreased an additional 23% (P<0.001) with significant variation among individuals (max+17%; min-94%). Decreases in methylation of ≥25% (vs. <25%) after discontinuation of supplementation were strongly associated with genotype: MTHFR CC vs. TT (adjusted odds ratio [aOR] 12.9, 95%CI 6.4, 26.0). The unexpected difference in DNA methylation between DNA extracted from coagulated and uncoagulated samples in response to folic acid supplementation is an important finding for evaluating use of folic acid and investigating the potential effects of folic acid supplementation on coagulation.
    PLoS ONE 12/2011; 6(12):e28144. DOI:10.1371/journal.pone.0028144 · 3.23 Impact Factor
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    ABSTRACT: To assess the influence of individual methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase A2756G polymorphisms on the change of serum folate concentration in response to different dosages and durations of folic acid (FA) supplementation in hypertensive Chinese adults. A total of 480 patients with mild or moderate essential hypertension were randomly assigned to three treatment groups: (a) enalapril only (10 mg, control group); (b) enalapril FA tablet [10 : 0.4 mg (10 mg of enalapril combined with 0.4 mg of FA), low-FA group]; (c) enalapril FA tablet (10 : 0.8 mg, high-FA group), once daily for 8 weeks. Individual serum folate levels were measured at baseline, and at 4 and 8 weeks posttreatment. After 4 or 8 weeks of treatment, increases in serum folate were seen across all genotypes and FA dosage groups. However, compared with patients with 677CC genotype, those with CT or TT genotype in the low-FA group and TT genotype in the high-FA group still had significantly lower folate concentrations, particularly women. In the low-FA group, patients with CT or TT genotype showed an attenuated response compared with those with CC genotype (median ratio of folate at week 8 to that at baseline: CC,1.953 vs. CT,1.755 or TT,1.637, P<0.01 for both). Such an attenuated response was not observed in the high-FA group. Yet, only in the high-FA group did serum folate appear to reach a plateau after 4 weeks of treatment in all three MTHFR 677 genotypes and the methionine synthase 2756 AG/GG genotype. We demonstrated that MTHFR C677T polymorphisms can not only affect serum folate levels at the baseline and post-FA treatment, but also therapeutic responses to various dosages and durations of FA supplementation.
    Pharmacogenetics and Genomics 08/2011; 22(6):421-8. DOI:10.1097/FPC.0b013e32834ac5e8 · 3.45 Impact Factor
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