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T Polymorphism in Young Women1,2
Food Science and Human Nutrition Department, University of Florida, and * General Clinical Research Center, University of Florida, Gainesville, FL 32611
3 To whom correspondence should be addressed. E-mail: lbbailey{at}mail.ifas.ufl.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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T polymorphism on folate and homocysteine response in nonHispanic women consuming a low folate diet followed by a diet providing the Recommended Dietary Allowance (RDA) for folate. Women (aged 20–30 y old) with either the TT (n = 19) or CC (n = 22) MTHFR 677CT genotype participated in a folate depletion-repletion study (7 wk, 115 µg dietary folate equivalents (DFE)/d; 7 wk, 400 µg DFE/d). Overall serum folate decreased (P < 0.0001) during depletion and increased (P < 0.0001) during repletion with lower (P = 0.03) postdepletion serum folate in women with the TT versus CC genotype. Folate status was low (serum folate < 13.6 nmol/L) in more women with the TT (59%) compared with the CC genotype (15%) postdepletion. Red blood cell folate for all subjects decreased during depletion (P < 0.0001) and repletion (P = 0.02) with lower (P = 0.04) red blood cell folate in women with the TT compared with the CC genotype postrepletion. Homocysteine increased (P < 0.0001) for both genotype groups postdepletion and decreased (P = 0.02) postrepletion for the CC genotype group only. Homocysteine concentrations tended to be higher (P = 0.09) in the TT versus CC genotype group postdepletion and postrepletion. These data suggest that the MTHFR 677CT polymorphism negatively affects the folate and homocysteine response in women consuming low folate diets followed by repletion with the RDA. These results may be important when evaluating the impact of the MTHFR 677CT polymorphism in countries in which low folate diets are chronically consumed.
KEY WORDS: • folate • 5'10-methylenetetrahydrofolate reductase • genotype • young women
The enzyme methylenetetrahydrofolate reductase (MTHFR)3 converts 5,10-methyleneTHF to 5-methylTHF, the folate coenzyme required for the remethylation of homocysteine to methionine. A base transition (CT) at position 677 in the gene that codes for MTHFR causes alanine to be replaced by valine in the MTHFR enzyme, which leads to impaired enzyme stability and reduced activity under conditions of low folate concentration (1,2). The MTHFR 677CT polymorphism affects a large percentage of the population with an estimated frequency of 
12% for the TT genotype with considerable variation between different ethnic groups (3,4).
Data from observational studies in populations in which folate intake is less than adequate indicate that individuals that are homozygous for the MTHFR 677CT polymorphism have lower blood folate (5,6) and higher plasma homocysteine concentrations (6–8) than those with the CC genotype. Chronic consumption of low folate diets by women of reproductive age with the TT genotype for the MTHFR 677CT polymorphism may have increased risk of impaired pregnancy outcome including neural tube defects (NTD) (9). The average folate intake in countries that do not practice folic acid fortification is 50% of the folate RDA of 400 µg dietary folate equivalents (DFE)/d and is associated with low blood folate (<13.5 nmol/L) (10) and elevated plasma homocysteine concentrations (>14 µmol/L) (11). Of particular concern are individuals with the TT genotype for the MTHFR 677CT polymorphism who chronically consume folate-inadequate diets as illustrated by recent cross-sectional studies of European population groups (6,12). In these studies (6,12) individuals with the TT genotype had low mean serum folate concentrations [10.4 nmol/L (12) and 6.3 nmol/L (6)] and elevated mean plasma homocysteine concentrations [21.3 µmol/L (12) and 17.1 µmol/L (6)]. Impaired folate status is associated with abnormal fetal growth and development (9) and increased risk of pregnancy complications (13), and periconceptional folic acid supplementation reduces NTD risk (14). The metabolic basis for these observations has not been definitively established but may relate to the role of folate in nucleotide biosynthesis (15), DNA methylation (16,17) and/or maintenance of normal homocysteine concentration (18).
There are no genotype-specific Dietary Reference Intakes (DRI) and data are insufficient to conclude that consumption of the current RDA for folate is sufficient to maintain normal folate status in individuals with the MTHFR 677CT polymorphism (11). The present study was designed to evaluate the effect of the MTHFR 677CT polymorphism on folate status response in young nonHispanic women of reproductive age consuming a moderately low folate diet followed by repletion with the current RDA. The results of this study provide data that may be important in future revisions of the folate RDA in which MTHFR genotype is considered.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Nonpregnant healthy women, aged 20–30 y old, were recruited and screened for this study. Only women with the CC or TT MTHFR 677 genotype were eligible. Exclusion criteria included chronic use of tobacco and alcohol products, use of all medications including oral contraceptives, current use of vitamin-mineral supplements, history of chronic disease or major surgery, >120% of ideal body weight [estimated from height, allowing for 45.36 kg (100 lb) for the 1st 1.52 m (5 ft) of height and 2.27 kg (5 lb) for each 2.54 cm (1 in) over 1.52 m (5 ft)] and abnormal blood chemistry profile. Ninety-three percent of the subjects reported their ethnicity to be nonHispanic white and 7% nonHispanic black. Forty-one women (19 TT, 22 CC) completed the depletion phase of the study (7 wk), and 20 women (10 TT, 10 CC) completed the entire depletion-repletion protocol (14 wk). A subgroup of subjects in a second study did not continue with the repletion phase. Serum and red blood cell folate, and plasma vitamin B-12, pyridoxal phosphate and homocysteine concentrations were normal at baseline for all subjects (i.e., 
7 nmol/L, 317 nmol/L, 125 pmol/L, 20 nmol/L and 
14 µmol/L, respectively). The University of Florida Institutional Review Board approved the study and written informed consent was obtained from each subject.
Experimental design and diet.
Subjects adhered to a depletion-repletion diet-controlled protocol divided into two consecutive periods of 49 d (7 wk) each (Fig. 1). Subjects consumed a low folate diet providing 115 ± 20 µg DFE/d during the 1st 7 wk of the study. The repletion diet consisted of a combination of the depletion diet plus folic acid and provided 400 µg DFE/d [115 + 285 µg DFE (168 µg folic acid x 1.7 = 285 µg DFE)] (11). The diets included conventional foods served as a 5-d menu cycle. Because the majority of commercially available cereal-grain products in the U.S. are enriched with folic acid, all food items containing cereal-grain products were prepared onsite using unenriched flour purchased from Kansas State University (Manhattan, KS). Foods made with the unenriched flour included waffles, pancakes, blueberry muffins, pita bread, biscuits, brownies, cookies, cakes and pizza crust. Several imported food items made with unenriched flour were also used. A limited selection of canned low folate vegetables were used, each of which was boiled three times and the cooking liquid discarded after each boiling to further reduce folate content. The nutrient content of the diet was estimated using the Minnesota Nutrient Data System (Version 4.03; Nutrition Coordinating Center at the University of Minnesota, Minneapolis, MN). The folate content of the diet was measured microbiologically (19,20) following a trienzyme extraction procedure (21). The diet provided an average energy intake of 9.87 MJ (2358 kilocalories/d; 63% carbohydrate, 11% protein and 26% fat). The subjects consumed a custom-formulated supplement (Westlab Pharmacy, Gainesville, FL) with breakfast and dinner to provide the RDA for all nutrients that were not met by the diet alone with the exception of folate and choline. The choline content of the diet was analyzed (22) and provided 285 mg/d (67% of the Adequate Intake) (11). The loss of water-soluble vitamins was assumed to be 100% from vegetables that were boiled to reduce their folate content and were accounted for in the supplement formulation if the loss prevented the diet from achieving 100% of the RDA. In addition, a separate calcium citrate supplement (Citracal; Mission Pharmacal, San Antonio, TX) provided 200 mg of calcium. Body weights were maintained at ±5% of baseline by modifying intake of nonnutritive calorically-dense menu items.
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Fasting venous blood samples for serum and red blood cell folate and plasma homocysteine measurements were obtained weekly (Fig. 1). Health status was assessed at baseline, wk 7 and wk 14 by monitoring blood chemistry and hematologic indices, including a complete blood count with differential (Quest Diagnostic Laboratories, Gainesville, FL). Human chorionic gonadotropin was measured biweekly to confirm nonpregnant status (Quest Diagnostic Laboratories).
Whole blood was collected in EDTA tubes for red blood cell folate determination (Vacutainer; Becton Dickinson, Rutherford, NJ), diluted 1:20 with 1 g/L ascorbic acid solution, incubated at room temperature for 30 min and frozen (-30°C) prior to analysis. Plasma for homocysteine concentration was obtained from whole blood that had been immediately placed on ice and centrifuged within 1 h of collection (2000 x g, 30 min, 4°C).
Analytical procedures.
The folate concentrations of blood specimens were determined using the Lactobacillus casei microbiological assay in a 96-well microplate system adapted from Tamura (19) and Horne and Patterson (20). The intra- and interassay CV for the microbiological assay were 8.7 and 7.1%, respectively. Plasma homocysteine concentrations were determined using a modification of the method of Vester and Rasmussen (23) using an isocratic HPLC system with fluorescence detection. A Dionex DX 500 chromatography system was used (Pump GP40, Universal Interface UI20, and autosampler AS3500; Dionex, Sunnyvale, CA; FD300 dual monochromator fluorescence detector; SpectroVision, Concord, MA). The fluorescence intensities were measured with excitation at 381 nm and emission at 515 nm. The intra- and interassay CV for the HPLC assay were 2.4 and 5.4%, respectively.
Determination of MTHFR 677CT genotype.
Genomic DNA was extracted from the leukocyte layer using a commercially available kit (Bio-Rad Laboratories, Hercules, CA). The presence of the MTHFR 677CT mutation was determined by PCR followed by restriction enzyme analysis with Hinf1 (1).
Statistical methods.
One-way ANOVA was used to test for differences in all indicators including serum and red blood cell folate, and plasma homocysteine concentrations at baseline. To account for subject variability on entry into the study, analysis of covariance was used to evaluate genotype group differences between all indicators at wk 7 and wk 14 with adjustment for either baseline or wk 7 values. Least-square (LS) means were used to describe the magnitude of the differences between each group. As a secondary analysis, ANOVA was performed on the raw and percent change values from wk 0 to wk 7, wk 7 to wk 14, and wk 0 to wk 14 for serum and red blood cell folate and plasma homocysteine concentrations. The percent change is the average of each individual’s value over a given time period, 0–7, 7–14 or 0–14 wks. A 2 x 2 contingency table was constructed and Fischer exact test used to evaluate serum folate depletion status by subject genotype.
The strength of the relationships between the dependent variables at each point in time (wk 0, 7 and 14) was examined by evaluating Pearson correlations. Regression and Pearson correlation techniques were used to evaluate the strength of the relationship between each status indicator over time during the depletion and repletion phases. Specifically, linear regression was used to determine the slope of parameters for each variable for each subject. Correlations of combinations of these coefficients (e.g., plasma homocysteine and serum folate concentrations) were then determined to assess the magnitude of the relationship. For all comparisons, the 
level was set a priori at 0.05. All statistics were computed using SAS 8.00 (Cary, NC). Data are expressed as mean ± SD for unadjusted means and mean ± SEM for LS adjusted means.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Serum folate concentration did not differ at baseline between subjects with the TT genotype compared with the CC genotype (41.5 ± 19.7 versus 52.2 ± 22.4 nmol/L, respectively; P = 0.12) (Table 1). Decreases (P < 0.0001) in serum folate concentration (% change, mean ± SD) were observed in response to folate depletion for subjects overall (59 ± 16%) and by genotype (57 ± 15 and 61 ± 16% for CC and TT, respectively) (Fig. 2). Postdepletion (wk 7), there was a higher (P = 0.03) serum folate concentration in subjects with the CC compared with the TT genotype (LS mean 19.5 ± 1.2 versus 15.3 ± 1.3 nmol/L, respectively) (Table 1). A greater (P = 0.0075) proportion of subjects with the TT genotype (59%) had low folate status (serum folate < 13.6 nmol/L) compared with the CC genotype (15%) postdepletion.
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Red blood cell folate.
Subjects with the TT genotype tended to have a lower (P = 0.06) mean red blood cell folate concentration at baseline than subjects with the CC genotype (Table 1). The percent change in red blood cell folate concentration for all subjects decreased (P < 0.0001) by 18 ± 15% during the depletion phase of the study.
The red blood cell folate concentration of subjects with the TT genotype continued to decrease (17 ± 19%; P = 0.02) during repletion in contrast to no response detected for subjects with the CC genotype. Postrepletion, the red blood cell folate concentration of subjects with the TT genotype was lower (P = 0.04) than subjects with the CC genotype (Table 1). Subjects with the TT genotype tended to have a lower (P = 0.06) red blood cell folate concentration than subjects with the CC genotype at wk 14 when adjusted for baseline values. Over the entire 14-wk protocol red blood cell folate concentration decreased (P < 0.01) for both genotype groups (TT: -33 ± 17%; CC: -25 ± 22%).
Plasma homocysteine.
The overall and by genotype plasma homocysteine concentrations increased (P < 0.0001) in response to folate depletion (Table 1, Fig. 2). Plasma homocysteine concentration increased by 62 ± 51% (P < 0.0001) for subjects with the TT genotype and 43 ± 32% (P < 0.0001) for subjects with the CC genotype during depletion. Women with the TT genotype tended to have a higher (P = 0.09) mean homocysteine concentration postdepletion than women with the CC genotype (Table 1). Subjects with the TT genotype tended to have a greater (P = 0.09) raw change in homocysteine concentration during depletion than subjects with the CC genotype (+3.9 ± 3.0 versus +2.5 ± 1.7 µmol/L, respectively). These increases in plasma homocysteine concentration paralleled decreases in serum folate during depletion (Fig. 2).
In response to folate repletion, plasma homocysteine concentration for subjects with the CC genotype decreased (P = 0.02) (Table 1). An inverse correlation was detected for serum folate and plasma homocysteine concentrations for both the TT and CC genotype groups during depletion (Fig. 2) (r = -0.05 and r = -0.45, respectively)(P = 0.04). The homocysteine concentration of subjects with the TT genotype was higher (P = 0.09) than that of subjects with the CC genotype postrepletion (Table 1). An increase (P = 0.004) (% change, mean ± SD) in plasma homocysteine over the entire 14-wk protocol was detected for subjects with the TT genotype (36 ± 29%), but not the CC genotype (14 ± 26%) (P = 0.11). When adjusted for wk 0, the LS mean for homocysteine (µmol/L) was higher (P = 0.04) at wk 14 for subjects with the TT genotype versus the CC genotype (8.83 ± 0.49 and 7.29 ± 0.49, respectively).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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T polymorphism on folate status response to moderate folate depletion and repletion with the current RDA. The dietary folate depletion protocol used was successful in attaining low folate status similar to that observed in European population groups in which dietary folate intake is 200 µg/d (6,24). For example, in a recent observational study conducted in the UK (24), the overall mean plasma folate and homocysteine concentrations at baseline were 17.7 nmol/L and 10.2 µmol/L, respectively, which are comparable to the values attained in the present study following folate depletion (17.6 nmol/L and 9.6 µmol/L, respectively).
Individuals with the TT genotype in the current study were less capable of maintaining normal blood folate concentration as evidenced by the greater percentage of this genotype group with low serum folate concentration (<13.6 nmol/L) (10) compared with the CC genotype postdepletion. The mean plasma homocysteine concentration was 3 µmol/L higher in subjects with the TT genotype with low folate status (<13.6 nmol/L) postdepletion than in subjects with the CC genotype. The data from the present study, in which nutrient intake was controlled, support the conclusion that folate deficiency alone is sufficient to negatively impact plasma homocysteine concentration in individuals with the TT genotype. The magnitude of this difference in plasma homocysteine between genotype groups may have been greater if the low folate diet had been consumed longer than 7 wk (6,12). For example, in observational studies of European population groups in which low folate diets are chronically consumed, the mean homocysteine concentration of individuals with the TT genotype ranges from 4 to 6 µmol/L higher than in individuals with the CC genotype [14.7 versus 21.3 (12) and 12.9 versus 17.1 (6)].
Differences in the homocysteine response to repletion with 400 µg DFE/d were observed between genotype groups. In the current study, folate repletion was insufficient to decrease the mean plasma homocysteine concentration in women with the TT genotype. In contrast, a change in homocysteine concentration occurred in response to folate repletion in women with the CC genotype. The percent increase in homocysteine from baseline to the end of the study was seen only for subjects with the TT genotype.
Changes in red blood cell folate concentration respond very slowly to reductions in folate intake but parallel changes in liver folate concentration (25). In the present study, red blood cell folate concentration continued to decrease during the repletion period in the TT genotype group only. Postrepletion, red blood cell folate concentration was lower in women with the TT genotype compared with the CC genotype suggesting that the TT genotype may have a greater negative effect on tissue stores of folate. In population groups in which red blood cell folate concentration is marginal due to chronic consumption of a low folate diet, the negative impact of the TT genotype may have important health-related consequences. Of particular concern in women of reproductive age is the inverse association between NTD risk and red blood cell folate concentration (26).
Data from a 14-wk controlled depletion-repletion metabolic study designed to evaluate the influence of the MTHFR polymorphism and folate status in young Mexican American women were recently published by Guinotte et al. (27). When the findings from the present study were compared with those of Guinotte et al. (27), ethnicity appeared to be a factor that may affect the folate and homocysteine status response to folate depletion (7 wk, 135 µg DFE/d) and repletion (7 wk, 400 µg DFE/d) in women with the CC versus TT MTHFR genotype. The ethnicity of the women in the present study was 93% nonHispanic white and 7% nonHispanic black compared with 100% Hispanic (Mexican American origin) in the Guinotte et al. (27) study. Baseline homocysteine concentration in women with the TT and CC genotypes in the present study was considerably higher than values reported by Guinotte et al. (27) in Mexican American women [7.1 versus 5.4 (TT) and 6.3 versus 5.3 (CC) µmol/L, respectively). The lower baseline homocysteine concentration in the Guinotte et al. (27) study relative to the present study could not be attributed to higher serum folate concentration, which was 10 and 20 nmol/L lower at baseline in Mexican American women with the TT and CC genotypes, respectively (27). The nonHispanic women in the present study were more responsive to the 400 µg DFE/d folate repletion diet than the Mexican American women (27) based on a 100% higher mean increase in serum folate (6.8 versus 3.2 nmol/L, respectively) postrepletion. Data from the National Health and Nutrition Examination Survey support the conclusion that Mexican American women have lower plasma homocysteine and serum folate concentrations after controlling for dietary intake compared with nonHispanic women (28–30). The basis for these apparent ethnic differences between blood folate and plasma homocysteine concentrations is unknown but may be due to other genetic differences that affect folate and homocysteine metabolism.
In addition to ethnicity, age may also negatively influence folate status (31). Our research group previously conducted a folate depletion study in elderly women (aged 60–85 y old) in which a low folate diet (118 µg DFE/d), comparable to that used in the present study, (115 µg DFE/d) was consumed for 7 wk (32). The mean serum folate concentration of the elderly women postdepletion was 11.3 compared to 17.6 nmol/L in the young women even though serum folate values [45.7 ± 27 (30) versus 47.2 ± 21.7] were comparable. In the present study, none of the young women developed a severe folate deficiency (serum folate concentration < 7 nmol/L) (10) following consumption of the low folate diet. In contrast, 21% of elderly subjects in our previous study were severely folate deficient by wk 7 suggestive of a negative influence of aging on the folate status response to a low folate diet (32). Increased age coupled with the presence of the MTHFR 677CT polymorphism may have an additive effect on folate status. The elderly women with the TT genotype for the MTHFR 677CT polymorphism (33) had a greater decrease (P = 0.04) in serum folate concentration during depletion compared with a subset of young women with the TT genotype in the current study (unpublished data).
In summary, the findings of the current study indicate that nonHispanic women of reproductive age with the TT genotype for the MTHFR 677CT polymorphism who consume low folate diets are at greater risk for impaired folate status than women with the CC genotype. Of particular concern is the potential negative impact of chronic consumption of low folate diets coupled with the TT genotype for the MTHFR 677CT polymorphism on reproductive health. Future metabolic studies designed to evaluate the adequacy of folate intake and influence of the MTHFR 677CT polymorphism on folate and homocysteine status should consider the potential effects of ethnicity and age.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported in part by USDA-NRI Grant #00–352009102, USDA-NRI Grant #00–35200–9113, NIH DK Grant #56724, and NIH GCRC Grant #RR00082.
4 Abbreviations used: DFE, dietary folate equilavents; DRI, Dietary Reference Intakes; LS, least squares; MTHFR, 5'10-methylenetetrahydrofolate reductase; NTD, neural tube defect; RDA, Recommended Dietary Allowance.
Manuscript received 1 July 2003. Initial review completed 6 September 2003. Revision accepted 14 September 2003.
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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