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Original Research Communication |
T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample1,2,3
1 From the Department of Chronic Disease Epidemiology, National Institute of Public Health and the Environment, Bilthoven, Netherlands (AdB and WMMV); the Laboratory of Pediatrics and Neurology, University Medical Center Nijmegen, Nijmegen, Netherlands (AdB, NMJvdP, SGH, FJMT, and HJB); the Scientific and Technical Institute of Nutrition and Food, U557 INSERM/U1125 INRA/ISTNA-CNAM, Paris (AdB); and the LOCUS for Homocysteine and Related Vitamins, University of Bergen, Bergen, Norway (A-LB-M).
2 Supported by grant no. 96.147 from the Netherlands Heart Foundation. HJ Blom is an established investigator of the Netherlands Heart Foundation (grant no. D97.021). 3 Address reprint requests to M Verschuren, Department of Chronic Disease Epidemiology (CZE, Pb 101), National Institute of Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, Netherlands. E-mail: wmm.verschuren{at}rivm.nl.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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T polymorphism decreases the enzyme’s activity. Objective: The objective of the study was to assess the effect of the polymorphism on the relations among folate intake, plasma folate concentration, and total plasma homocysteine (tHcy) concentration.
Design: The design was a cross-sectional analysis in a random sample (n = 2051) of a Dutch cohort (aged 20–65 y).
Results: At a low folate intake (166 µg/d), folate concentrations differed significantly among the genotypes (7.1, 6.2, and 5.4 nmol/L for the CC, CT, and TT genotypes, respectively; P for all comparisons < 0.05). At a high folate intake (250 µg/d), folate concentrations in CT and CC subjects did not differ significantly (8.3 and 8.6 nmol/L, respectively, but were significantly higher (P = 0.2) than those in TT subjects (7.3 nmol/L; P = 0.04). At a low folate concentration (4.6 nmol/L), TT subjects had a significantly higher (P = 0.0001) tHcy concentration than did CC and CT subjects (20.3 compared with 15.0 and 14.1 µmol/L, respectively), whereas at a high folate concentration (11.9 nmol/L), the tHcy concentration did not differ significantly between genotypes (P > 0.2; <13.1 for all genotypes). The relation between folate intake and tHcy concentration had a pattern similar to that of the relation between plasma folate and tHcy concentrations.
Conclusions: At any folate intake level, TT subjects have lower plasma folate concentrations than do CT and CC subjects. Yet, at high plasma folate concentrations, tHcy concentrations in TT subjects are as low as those in CT and CC subjects.
Key Words: Methylenetetrahydrofolate reductase • MTHFR • folate intake • plasma folate concentration • plasma homocysteine concentration • total homocysteine • tHcy • metabolism • Dutch population
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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T mutation in the gene that encodes for MTHFR (3) decreases the enzyme’s activity (3, 4). The prevalence of this variant is relatively high in the general population; eg, the prevalence of homozygosity (TT) is 5–15% in several white populations (5).
The 677CT polymorphism is associated with a higher plasma total homocysteine (tHcy) concentration (3, 6), which is most pronounced in subjects with the TT genotype who have a marginal folate status (7). The polymorphism is also associated with a lower plasma folate concentration (8–16). These metabolic changes are postulated to modify the risk of chronic diseases, including cardiovascular disease (17, 18), cancer (19), and dementia (20, 21), and the risk of neural tube defects (8, 22). Therefore, it is important to have detailed information on the consequences of the 677CT genotype for the relations between folate intake, plasma folate, and tHcy. Yet the influence of the 677CT genotype on the relation between folate intake and plasma folate and on that between folate intake and plasma tHcy has only scarcely been investigated (8, 23).
With the data from a large cross-sectional, population-based study, we described the effect of the MTHFR 677CT mutation on the relation between folate intake and plasma folate and on the subsequent relation between plasma folate and tHcy. Data on the effect of the genotype on the relation between folate intake and tHcy are presented as well, to interpreted studies that have data only on the relation between folate intake and tHcy.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Data collection
Respondents completed 2 self-administered questionnaires: a general questionnaire and a semiquantitative food-frequency questionnaire (FFQ). Subsequently, trained research assistants performed a physical examination at the Municipal Health Services of the three above-mentioned cities where subjects were located.
From the general questionnaire, we extracted information on sex, age, and smoking. The semi-quantitative FFQ provided information on dietary habits. This questionnaire’s relative validity for food groups was tested against twelve 24-h recalls, and its reproducibility for food groups was tested by using 2 questionnaires administered 12 mo apart. Overall, the relative validity and the reproducibility of this questionnaire were sufficient and similar to those of other FFQs (26). We calculated the intake of folate and also of other nutrients (vitamins B-2, B-6, and B-12 and methionine) that are closely related to folate (27). Furthermore, we extracted data on the consumption of alcoholic beverages. The FFQ did not collect information on the doses and contents of vitamin supplements. Hence, to reduce the misclassification of B vitamin intake, we excluded from all analyses subjects who used supplements that might have contained B vitamins (217 men and 371 women).
Blood sampling and biochemical determinations
During the physical examination, nonfasting venous blood samples were obtained. The samples were collected in evacuated tubes containing 7.5% K3-EDTA (Safety-Monovette tubes; Sarstedt, Tilburg, Netherlands) and centrifuged within 1 h (10 min at 3000 x g at room temperature). After centrifugation, the plasma, red blood cells, and white blood cells were separated and stored at -20°C or -80°C. The blood samples were stored at room temperature before centrifugation, but we found that this led to only a small increase in the measured tHcy concentration (24).
We measured the tHcy concentration, including the protein-bound and nonprotein-bound fractions of homocysteine, by using HPLC with fluorescence detection as described by Fiskerstrand et al (28), with some modifications (29). The within- and between-run CVs were 3.2% and 8.6%, respectively.
Plasma folate concentration was determined with the use of a Lactobacillus casei microbiologic assay (30), and plasma vitamin B-12 concentration was assessed with a Lactobacillus leichmannii assay (31). Both the folate and the vitamin B-12 assays were adapted to a microtiter plate format and carried out by a robotic workstation (Microlab AT Plus; Hamilton, Bonaduz, Switzerland). The within- and between-run CVs were 4.3% and 10.4% for folate and 1.1% and 1.7% for vitamin B-12.
DNA was extracted from frozen peripheral blood lymphocytes by a salting-out procedure. The presence of the 677CT mutation was assessed by polymerase chain reaction, which was followed by restriction enzyme analysis with HinFI (3). For 182 men and 204 women, the DNA extraction or genotyping was unsuccessful. The genotype distribution was in Hardy-Weinberg equilibrium.
Statistical analysis
Because of the exclusion of B vitamin supplement users (n = 588) and of subjects with a missing MTHFR genotype (n = 386), all analyses are based on data for 2051 men and women. The distributions of the plasma concentrations of tHcy, folate, and vitamin B-12 and the intake of all nutrients were skewed with a long tail toward higher values, and thus natural logarithmic transformations were applied to normalize these distributions. Inverse transformations were performed to provide geometric means and 95% CIs. Geometric means are provided throughout this report. After logarithmic transformation, the intakes of the nutrients (B vitamins and methionine) were adjusted for energy according to the method of Willett et al (32) as described elsewhere (33).
Mean geometric values of B vitamin and methionine intakes and of plasma concentrations of folate, vitamin B-12, and tHcy were calculated by MTHFR genotype (CC, CT, and TT), and P values for trends were calculated with univariate linear regression analyses with genotype as the independent variable.
The role of the 677CT polymorphism in the relations between 1) folate intake and plasma folate concentration, 2) plasma folate and tHcy concentration, and 3) folate intake and tHcy concentration was described for men and women together, because no modification of effect by sex was observed for these relations. Modification of effect by the polymorphism in the above relations was evaluated in linear regression models with the inclusion of the appropriate interaction terms, eg, folate intake x genotype. A P value < 0.05 for the interaction term was considered to indicate a significant interaction.
Genotype-stratified relations were adjusted for age and sex. In multiple regression models, we also adjusted for alcohol consumption (drinks/d) and smoking (no or yes). Furthermore, we adjusted for vitamin B-12 intake in the relation with folate intake as explanatory variable and for plasma B-12 in the relation with plasma folate as explanatory variable. Because we did not have plasma levels of vitamins B-2 and B-6 and methionine, we could only adjust the associations for intakes of these nutrients.
To test whether the ß coefficients differed significantly among the 3 genotypes, we calculated by hand the test statistic (ß1 - ß2)/SEß1 - ß2, which follows a Student’s t test distribution. The SE of ß1- ß2 was calculated with the use of the following formula: SEß1 - ß2 = 
[(SEß1)2+ (SEß2)2]. The 2-sidedP value of this statistic was derived from a table giving the percentile values of thet distribution (34). To account for multiple comparison, we multiplied thisP value by 3.
The mean adjusted plasma folate or tHcy concentrations (and 95% CIs) for each genotype within tertiles (based on the total population, rather than being genotype-specific) of folate intake or plasma folate concentrations were calculated by analyses of covariance, as implemented in the general linear model procedure (SAS Institute Inc, Cary, NC). Differences in mean concentrations compared with a referent category were tested with the use of Bonferroni’s adjustment for multiple comparisons.
Findings were considered significant if the 2-sided P value was < 0.05. Data were analyzed with SAS statistical software, version 8.1 (SAS Institute Inc).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The plasma folate concentration was inversely associated with the presence of a T allele. Compared with CC subjects, TT subjects had an average plasma folate concentration 1.7 nmol/L lower and CT subjects had an average plasma folate concentration 0.8 nmol/L lower. The prevalence of a low plasma folate concentration (defined as < 4.5 nmol/L) increased with the presence of the mutation: 8% in CC subjects, 11% in CT subjects, and 23% in TT subjects. There was no association between the 677CT polymorphism and the plasma vitamin B-12 concentration.
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The effect of theMTHFR677C T mutation on the slopes of the relations among folate intake and plasma folate and tHcy concentrations
The P value of the interaction term folate intake x genotype in the regression model describing the continuous relation between folate intake and plasma folate concentration was 0.02; the interaction term plasma folate x genotype in the model describing the relation between plasma folate and tHcy was 0.0001, and the interaction term folate intake x genotype in the model describing the relation between folate intake and tHcy was 0.0001. Because of these interactions, we have stratified these relations to genotype.
The ß coefficients of the linear regression models of the above described relations are shown in Table 2. These ß coefficients express the change in, respectively, logarithmically transformed plasma folate (nmol/L) and logarithmically transformed tHcy (µmol/L) that is associated with a 1-unit change in logarithmically transformed folate intake (µg/d) or logarithmically transformed plasma folate concentration (nmol/L). Because of this logarithmic transformation of the x variable as well as the y variable, the interpretations of these coefficients is as follows: a 1% change in the x variable corresponds to a ß% change in the y variable. For example, a 1% increase in folate intake is associated with a 0.47% increase in plasma folate concentration, according to the first coefficient in Table 2.
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T mutation and the relation between folate intake and plasma folate concentration
). The steepest increase in plasma folate concentration with an increasing folate intake was observed in TT subjects (ß = 0.77), whereas the least steep slope was observed in CC subjects (ß = 0.47). Multiple adjustment (age, sex, alcohol consumption, smoking, and intake of vitamins B-2, B-6, and B-12 and methionine) attenuated the slopes for CC and TT subjects, but augmented the steepness of the slope in CT subjects. The slope in CT subjects differed significantly from that in CC subjects (P < 0.015).
The mean adjusted (for age; sex; intake of vitamins B-2, B-6, and B-12 and methionine; alcohol consumption; and smoking) plasma folate concentration for each genotype per tertile of folate intake is shown in Figure 1. The mean folate intake in the lowest tertile was 166 µg/d (minimum, 102; maximum, 190); that in the medium tertile was 205 µg/d (191–220), and that in the highest tertile was 250 µg/d (221–761). This figure illustrates both the above described steepness of the relation between folate intake and plasma folate and the effect of the genotype on the plasma folate concentration at a given folate intake. At a low folate intake, the plasma folate concentration of all genotypes differed significantly: CC compared with CT, P = 0.0005; CC compared with TT, P = 0.0001; and CT compared with TT, P = 0.03. At a medium folate intake, the plasma folate concentration differed significantly between CC and TT subjects (P = 0.0007) and between CC and CT subjects (P = 0.003), but not between CT and TT subjects (P = 0.2). At a high folate intake, the plasma folate concentrations in CC and CT subjects did not differ significantly (P = 0.9), but TT subjects had a lower plasma folate concentration than did CC (P = 0.006) and CT (P = 0.04) subjects, despite equally high folate intakes.
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T mutation and the relation between plasma folate and tHcy concentrations). The steepest decrease in tHcy with an increasing plasma folate concentration was observed in TT subjects (ß = -0.48), and the least steep slope was observed in CC subjects (ß = -0.17). All slopes differed significantly between the genotypes (P < 0.015). Additional adjustments for the intakes of vitamins B-2 and B-6 and methionine, plasma vitamin B-12 concentration, alcohol consumption, and smoking did not significantly change our results.
The mean adjusted (intake of vitamins B-2 and B-6 and methionine, plasma vitamin B-12 concentration, alcohol consumption, and smoking) tHcy concentration per tertile of the plasma folate concentration is shown in Figure 2. The mean plasma folate concentration in the first tertile was 4.6 nmol/L (minimum: 1.2, maximum: 6.2); that in the medium tertile was 7.5 (6.3–8.9) nmol/L, and that in the highest tertile was 11.9 (9.0–56.3) nmol/L. The figure shows the multiple adjusted results presented in Table 2: compared with CC and CT subjects, TT subjects had a steeper inverse relation between folate intake and tHcy. At a low plasma folate concentration, TT subjects had a significantly higher (P = 0.0001) tHcy concentration than did CC and CT subjects. Although the mean tHcy concentration in CT subjects was much lower than that in TT subjects, it was significantly higher (P = 0.03) than that in CC subjects. At a medium plasma folate concentration, the mean tHcy concentration in TT subjects remained the highest (P = 0.0001 for the comparison with CC subjects and P = 0.0003 for the comparison with CT subjects). The tHcy concentrations in CT and CC subjects no longer differed significantly (P = 0.6). At a high plasma folate concentration, none of the tHcy concentrations differed significantly (CC compared with CT, P = 0.99; CC compared with TT, P = 0.2; CT compared with TT, P = 0.3).
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T mutation and the relation between folate intake and tHcy concentrations). The multiply adjusted (age, sex, alcohol consumption, smoking, and intake of vitamins B-2, B-6, and B-12 and methionine) relation between folate intake and tHcy attenuated the slopes for all genotypes and they were no longer significantly different.
The mean adjusted (for intakes of vitamins B-2, B-6, and B-12 and methionine; alcohol consumption; and smoking) tHcy concentration per tertile of folate intake is shown in Figure 3. As shown in Table 2, the steepest inverse slope between increasing folate intake and tHcy was observed in TT subjects. At a low folate intake, TT subjects had the highest tHcy concentration (P = 0.0001 when compared with CC and CT subjects), and the mean tHcy concentration in CT subjects was also significantly higher than that in CC subjects (P = 0.02). At a medium folate intake, tHcy concentrations also differed significantly by genotype (CC compared with CT, P = 0.02; CC compared with TT, P = 0.0001; CT compared with TT, P = 0.0001). At a high folate intake, the tHcy concentrations in CC and CT subjects no longer differed significantly (P = 0.99); however, despite the equally high folate intake, TT subjects still had a significantly higher mean tHcy concentration than did CC and CT subjects (P = 0.0001).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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T polymorphism that have not been described in detail for a general population. First, at any folate intake level (including the highest level), TT subjects always had lower plasma folate concentrations than did CC or CT subjects. Second, CT subjects experienced an unfavorable effect of their T allele only when they had a low folate intake. Moreover, we confirmed a well-described gene x nutrient interaction; those with the TT genotype and a low plasma folate concentration or a low folate intake had higher tHcy concentrations than did CT and CC subjects. Conversely, at a high plasma folate concentration or a high folate intake, the difference in tHcy concentrations between the genotypes was small.
In the present study, 10% of the subjects were identified as homozygous for the 677CT mutation; heterozygotes accounted for 44% of the subjects. These values are similar to those reported in other white populations (5). The fact that we had a complete data set for a subsample of the original random sample did not render our sample less representative: the distribution of age, lifestyle factors, biological cardiovascular disease risk factors (ie, blood pressure and total and HDL-cholesterol concentrations) was equal for subjects who were (n = 2051) and were not (n = 974) included.
The intake of folate and other relevant nutrients was assessed with a semiquantitative FFQ validated for the intake of food groups predominantly contributing to the intake of the studied nutrients (ie, vegetables, bread, milk and milk products, meat, and potatoes) (35). Furthermore, folate intake correlated with the plasma folate concentration in the same magnitude (Spearman correlation: 0.27) as in other Dutch studies (36, 37). Plasma folate concentrations were somewhat lower than those measured in other Dutch populations (8, 36, 38, 39). This difference may be attributable to the different methods used to measure the folate concentration (40, 41); in addition, we excluded all B vitamin supplement users, and they had higher plasma folate concentrations (data not shown).
The majority of the blood samples obtained for the tHcy measurement were from nonfasting subjects. Consumption of a normal breakfast is associated with a lower tHcy concentration (42), and a protein-rich meal results in a higher tHcy concentration (43). Nevertheless, the type of foods eaten by our subjects before the sampling of blood is most likely to have been independent of the genotype. Furthermore, our data showed no significant difference between the tHcy concentration in subjects who had fasted before the blood collection and that in subjects who had not (24). In addition, whole blood was stored at room temperature for a maximum period of 1 h before centrifugation. Because of a continuous synthesis and transport of homocysteine in blood cells at room temperature (44, 45), the tHcy concentrations in our samples might on average have been 0.4 µmol/L higher, as was indicated by a stability study (24). The small artificial increase in tHcy did not affect the ranking of our subjects according to their tHcy concentration (24). We conclude that the validity of our tHcy data was not seriously affected by the above mentioned factors.
The product of MTHFR, 5-methyltetrahydrofolate, is the predominant circulating form of folate, whereas the enzyme substrate 5,10-methylenetetrahydrofolate is mainly found intracellularly (46, 47). Because the 677CT mutation results in a reduced specific enzymatic activity of MTHFR (
34% residual activity in TT and 71% residual activity in CT relative to CC; 48), the result of the presence of a T allele may be a lower plasma folate concentration. Indeed, many investigators have reported a lower plasma folate concentration in TT subjects than in CC subjects (8–16). We were able to investigate whether differences in folate intake could (partly) explain this observation after adjustment for potential confounders. We found that this was not the case: for each folate intake tertile (where folate intake was equal for all genotypes), the adjusted plasma folate concentrations in TT subjects were always lower than those in CC or CT subjects (Figure 1). A comparable finding was briefly mentioned in another cross-sectional study, but the results were not shown (16). Very recently, the influence of the MTHFR 677CT mutation on the response to dietary interventions was reported (23). The findings of those investigators, analogous to our results for low, medium, and high folate intakes (Figure 1), were that a gradient in plasma folate concentrations (CCCTTT) remained throughout the exclusion diet, the folate-rich diet, and the exclusion diet supplemented with 400 µg folic acid/d.
The observation that CT subjects have a lower plasma folate concentration than do CC subjects when folate intake is low has not been reported before. Yet, some researchers found that CT subjects in general had significantly lower mean plasma folate concentrations than did CC subjects (11, 13). In addition, in a finding analogous to the gene x nutrient interaction seen in our TT subjects, some researchers reported high tHcy concentrations in CT subjects with a low plasma or red blood cell folate concentration (5, 11). These findings imply that, to compensate for their T allele, CT subjects need more folate than do CC subjects. Once the folate intake of CT subjects is high, their plasma folate concentration is equal to that of CC subjects. This, however, is not the case in TT subjects.
Our findings confirm the suggestion that lower plasma folate concentrations in TT (or CT) subjects are not necessarily due to dietary insufficiencies but may reflect a direct effect of the MTHFR 677CT polymorphism (11, 16, 49). Extra dietary folate will likely counteract the effect of the TT genotype (23), as was seen in CT subjects. The extra amount required could not be estimated from this cross-sectional study because of the limited range of folate intake in TT subjects; only dose-finding trials can answer this question.
Findings of Guenther et al (50) explain why extra folate may protect subjects with 1 or 2 T alleles from low plasma folate and high tHcy concentrations. In a system with bacteria, they showed that a mutation homologous to the human MTHFR 677CT mutation was associated with an enhanced dissociation of flavin adenine dinucleotide (ie, the cofactor form of vitamin B-2). An optimal folate supply prevented the loss of flavin adenine dinucleotide and suppressed the inactivation of the enzyme (50).
The effect of the polymorphism on the relation between the plasma folate and tHcy concentration agrees with the findings in other studies (7, 11, 18, 51). So far, one other study has reported the modifying effect of the polymorphism on the relation between folate intake and the tHcy concentration (16). As in the present study, they found that, at a low folate intake, TT subjects had much higher tHcy concentrations than did CT and CC subjects. Alternatively, at high folate intakes, the tHcy concentration in TT subjects was similar to the concentrations in CT and CC subjects (16). These results agree with those in other trials, which show a steeper decrease in the tHcy concentration in TT subjects than in the concentrations in CT and CC subjects, in response to an increased folic acid intake (10, 23, 52).
In conclusion, this study describes an important gene x environment interaction in the general population. Our findings indicate that subjects with the 677CT mutation, especially those with the mutation in homozygous form, need more dietary folate to achieve a plasma folate concentration as high as that in CC subjects. Once CT subjects have reached a high plasma folate concentration, however, their tHcy concentration is not different from that in CC subjects. Future dietary dose-finding trials should indicate the level of folate necessary for TT subjects to achieve a high plasma folate concentration. We showed that an average intake of 250 µg/d is not sufficient. In light of this finding, a reconsideration of the current Dutch dietary recommendation for folate, which is set at 200–300 µg/d for adults (53), might be appropriate. This recommendation is estimated to be sufficient to cover the needs of most (97.5%) of the healthy population. However, for the 10% of the population with the TT genotype, this amount may not be sufficient.
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ACKNOWLEDGMENTS |
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T polymorphism. |
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K. P. Shelnutt, G. P. A. Kauwell, C. M. Chapman, J. F. Gregory III, D. R. Maneval, A. A. Browdy, D. W. Theriaque, and L. B. Bailey Folate Status Response to Controlled Folate Intake Is Affected by the Methylenetetrahydrofolate Reductase 677C->T Polymorphism in Young Women J. Nutr., December 1, 2003; 133(12): 4107 - 4111. [Abstract] [Full Text] [PDF]
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 R. Carmel, R. Green, D. S. Rosenblatt, and D. Watkins Update on Cobalamin, Folate, and Homocysteine Hematology, January 1, 2003; 2003(1): 62 - 81. [Abstract] [Full Text] [PDF]
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; CT subjects, 
. Means were adjusted for age, sex, smoking (no or yes), alcohol consumption (drinks/d), and intakes of vitamins B-2, B-6, and B-12 and methionine. Values with different superscript letters are significantly different, P < 0.05. For a comparison of genotypes at the same folate intake, tertiles were based on the distribution of the entire population; thus, the numbers of CC, CT, and TT subjects with low, medium, and high folate intakes were 308, 297, and 78; 310, 313, and 60; and 319, 296, and 68, respectively.
