© 1997 American Heart Association, Inc.
Articles |
The Effects of Folic Acid Supplementation on Plasma Total Homocysteine Are Modulated by Multivitamin Use and Methylenetetrahydrofolate Reductase Genotypes
From the Oregon Regional Primate Research Center, Beaverton (M.R.M., D.L.H., B.U.), Providence St Vincent Hospital (M.R.M., R.A.G., P.C.B., C.R.H., P.H.A.) and the Oregon Health Sciences University, Portland (M.R.M., P.B.D., D.L.H., R.A.G., P.C.B., C.R.H.), Ore; The Johns Hopkins University, Baltimore, Md (F.J.N.); Fox Chase Cancer Institute, Philadelphia, Pa (W.D.K., Q.R.L.); and Carle Foundation Hospital, Urbana, Ill (D.S.).
Correspondence to M.R. Malinow, MD, Scientist, Oregon Regional Primate Research Center, 505 NW 185th Ave, Beaverton, OR 97006. E-mail malinowr{at}ohsu.edu
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Abstract |
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Abstract Elevated concentration of plasma total homocysteine (tHcy) is a common risk factor for arterial occlusive diseases. Folic acid (FA) supplementation usually lowers tHcy levels, but initial tHcy and vitamin levels, multivitamin use, and polymorphisms in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR) may contribute to variability in reduction. We tested the effects of a 3-week daily intake of 1 or 2 mg of FA supplements on tHcy levels in patients with and without coronary heart disease (CHD) who were analyzed for the C677T MTHFR mutation. Prior multivitamin intake and baseline vitamin and tHcy levels were also compared with responsiveness to folate supplementation. Both dosages of FA lowered tHcy levels similarly, regardless of sex, age, CHD status, body mass index, smoking, or plasma creatinine concentration. In non–multivitamin users, FA supplements reduced tHcy by 7% in C/C homozygotes and by 13% or 21% in subjects with one or two copies of the T677 allele, respectively; the corresponding reductions were smaller in users of multivitamins. Moreover, T/T homozygotes had elevated tHcy and increased susceptibility to high levels of tHcy at marginally low plasma folate levels, as well as enhanced response to the tHcy-lowering effects of FA. Although other factors are probably involved in the responsiveness of tHcy levels to FA supplementation, about one third of heterogeneity in responsiveness was attributable to baseline tHcy and folate levels and to multivitamin use.
Key Words: homocyst(e)ine • gene mutations • vitamin therapy • arterial occlusive diseases
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Introduction |
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Numerous investigations have demonstrated that the concentration of plasma tHcy is elevated in patients with coronary, cerebral, or peripheral arterial occlusive diseases.1 2 3 4 Plasma/serum homocyst(e)ine [H(e)], or tHcy, is the sum of the concentration of the amino acid homocysteine and the homocysteinyl moieties of the disulfides homocystine and homocysteine-cysteine, whether free or bound to plasma proteins. Homocyst(e)inemia refers to plasma levels of tHcy; hyperhomocyst(e)inemia indicates elevated concentration of plasma/serum tHcy. A comprehensive meta-analysis of 27 studies relating elevated plasma tHcy levels and arterial occlusive diseases was consistent with a causal role of plasma tHcy in the pathogenesis of vascular disease.2 Thus, elevated levels of plasma tHcy are considered to be a common risk factor for arterial occlusive diseases,3 and this risk is graded across the concentration distribution of tHcy.2 FA supplementation (between 0.5 and 10 mg/d),5 6 7 as well as multivitamins containing, inter alia, 0.2 to 0.4 mg FA,8 9 reduces plasma tHcy concentrations. Further studies are required to elucidate the factors responsible for interindividual heterogeneity in responsiveness to folate supplementation. We hypothesized that allelic variations in the gene for MTHFR, an FA-related enzyme, as well as baseline tHcy and vitamin levels, may contribute to that heterogeneity. To test this hypothesis, the effects of a daily supplement of either 1 or 2 mg of FA for 3 weeks on plasma tHcy levels were examined in subjects with or without CHD who were homozygous, heterozygous, or null for the C677T mutation in the MTHFR gene. The modulating effects of multivitamin use and baseline tHcy and vitamin levels on responsiveness to FA supplementation in these subjects also were tested.
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Methods |
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Subjects were recruited from internal medicine or family practice physicians associated with Providence St Vincent Hospital (Portland, Ore), from a cohort of patients discharged with the diagnosis of ischemic heart disease (ICD 9 code 410-414), or were self-referred in response to advertisements. The study population included 317 unrelated men and women 45 to 85 years of age at the time of the initial interview. Subjects were excluded from the study if they had received medication(s) within 7 days that may have an effect on tHcy levels (ie, methotrexate, tamoxifen, anticonvulsants, bile acid sequestrants, or nitrous oxide anesthesia). Other exclusion criteria were missed laboratory appointments, ingesting
0.8 mg FA daily, or plasma creatinine levels 1.7 mg/dL. The study population was limited to 242 subjects in whom MTHFR genotyping was performed, thus fitting in with the main hypothesis of the study. All subjects were advised to continue with their usual medications, including multivitamins, throughout the observation. The study was approved by the Institutional Review Boards of Providence St Vincent Hospital and the Oregon Regional Primate Research Center. Case subjects were diagnosed more than 3 months previously with a history of acute myocardial infarction, angina pectoris documented by a cardiologist, percutaneous transarterial coronary angioplasty, or coronary bypass graft surgery (n=140). Control subjects had no history of CHD (n=102). Case and control subjects reported having no history of stroke, intermittent claudication, or peripheral arterial revascularization.
All subjects completed a medical history form, signed an informed consent form, and were then randomized to receive either 1 or 2 mg FA per day for 3 weeks. The need for a placebo group was obviated by previous data that demonstrated stability of tHcy and folate plasma levels during a 6-week interval.7 Subjects were requested to arrive at laboratory appointments in the fasting state (ie, no food after midnight) and were instructed not to take any vitamins on the morning of phlebotomy. During the first appointment, 1-mg FA tablets were given to the subjects, with appropriate instructions. During the second visit, subjects returned their remaining FA tablets for assessment of compliance.
Within 30 minutes of venous blood drawing, plasma was separated in a refrigerated centrifuge at 4°C for clinical chemistry and then frozen for analysis of tHcy by high-pressure liquid chromatography and electrochemical detection as described,10 11 with minor modifications (interassay CV=9.1%) (performed at Oregon Regional Primate Research Center by Dr Malinow). Plasma aliquots were protected from light and frozen at -20°C for radioimmunoassay of FA (CV=7.8%) and vitamin B12 (CV=5.4%) (Bio-Rad Quantaphase II, Bio-Rad Diagnostics) and for radioenzymatic assay of P5'P (CV=14.4%; American Laboratory Product Company, Buhlman Laboratories AG) (performed at Oregon Regional Primate Research Center by Dr Hess). The blood buffy-coat layer was separated, mixed with 3 drops of DMSO, and frozen at -20°C for analysis of the C677T MTHFR polymorphism (performed at Fox Chase Cancer Institute, Philadelphia, Pa, by Dr Kruger). After thawing, DNA was isolated by using Instagene Matrix (Bio-Rad Diagnostics). Isolated DNA was used as the template in a polymerase chain reaction, using 100 ng of the forward and reverse primers as previously described.12 The amplification reaction was performed in a 50-µL volume in 60 mmol/L Tris-HCl, 15 mmol/L (NH4)SO4, 200 µmol/L dNTP, and 5 units of Taq polymerase. The mixture was subjected to 30 cycles of amplification at 94°C for 30 seconds, 62°C for 30 seconds, and 72°C for 30 seconds. The polymerase chain reaction products were precipitated with ethanol and digested overnight with HinfI (New England Biolabs). The products were analyzed by 3% agarose gel electrophoresis.
Statistics
The distribution of study variables was examined using standard exploratory data analysis techniques for independent subjects. Logarithmic transformations were performed to improve normality in some of the study variables (BMI and plasma levels of tHcy, folate, vitamin B12, and P5'P). The distributions of study variables by case-control status was compared using 
2 tests for categorical variables and t test for continuous variables. Statistical significance of changes in tHcy and folate levels was assessed using paired t test. Plasma tHcy and folate levels were compared across categories of folate dose, multivitamin status, and MTHFR genotype using standard ANOVA techniques. Adjustment for potential covariates was carried out using multiple linear and stepwise regression. Mean tHcy decreases after folate supplementation were correlated with the number of T677 alleles in the MTHFR genotypes. All reported probability values are two-sided. Statistical analyses were conducted using SAS, version 6.10 (SAS Institute) and SigmaStat (Jandel Scientific).
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Results |
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The majority of participants (97.4%) were white. Ninety-nine subjects were habitual multivitamin users; intake of FA in current multivitamin users ranged between 0.1 and 0.53 mg/d (mean±SD, 0.384±0.063; n=72). Multivitamins usually contained, inter alia, 2 mg of vitamin B6 and 6 µg of vitamin B12. Multivitamin users reported their duration of intake as "many months" to "several years."
Most study participants (67%) returned unused FA tablets on their second laboratory visit. The number of remaining tablets was used for compliance assessment; data suggested that subjects consumed 99.7±10.6% of folate supplements.
Case subjects (58% of all study participants) were more likely to be male, older, and former smokers compared with the control group. Cases showed a higher prevalence of the T/T MTHFR genotype. Plasma tHcy was significantly higher in cases than in control subjects. The concentration of plasma vitamins was similar in both groups of subjects (Table 1
). Table 1 also shows data in subjects stratified by multivitamin intake. Compared with nonusers, users of multivitamins were leaner and had lower levels of tHcy and higher plasma levels of vitamins.
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FA supplementation was about equal in cases and control subjects; dosages of either 1 or 2 mg/d had similar effects on tHcy levels (Table 2). In multivitamin users, folate supplementation reduced initial plasma tHcy levels by <5% (P=not significant). In nonusers of multivitamins, FA supplementation reduced plasma tHcy levels by 10% to 14% (P<.0001). However, reduced levels were somewhat higher than the lower concentrations attained by folate supplementation in users of multivitamins.
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The ingestion of either 1 or 2 mg of FA increased plasma folate to approximately similar levels in users and nonusers of multivitamins. Consequently, the relative increases in plasma folate were smaller in users than in nonusers of multivitamins. The percent decrease in plasma tHcy was significantly correlated with percent change in plasma folate (r=.215, P<.01; not shown in tables). The magnitude and statistical significance of results were essentially similar after adjusting for age, log BMI, smoking, sex, CHD status, and plasma creatinine concentration (Table 2
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Current multivitamin users, compared with nonusers, had higher basal levels of folate, P5'P, and vitamin B12 (Table 1). The regression equations and index of correlations for log tHcy versus log plasma vitamin levels in all subjects demonstrated significant negative correlations between log basal tHcy and log plasma vitamin levels (Table 3). The correlation coefficients were -.134 (P<.18), .099 (P=.33), and -.179 (P<.08) in users of multivitamins, and -.432 (P<.001), -.148 (P=.08), and -.216 (P<.01) in nonusers, for log transformed levels of folate, P5'P, and vitamin B12, respectively (not shown in the tables).
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Data on effects of FA supplements stratified by multivitamin use in subjects with different MTHFR C677T genotypes are shown in Table 4. In subjects with the C/C genotype, the supplements reduced tHcy levels 3% to 7%. However, tHcy levels decreased 3% to 13% in subjects heterozygous (C/T) and about 10% to 21% in subjects homozygous for the T/T mutation. The effects of FA supplements were more marked in nonusers than in multivitamin users after stratification for the C677T MTHFR polymorphisms. Results observed when subjects were stratified according to their baseline folate concentration, ie, above or below the sample geometric mean (16.1 µmol/L), are shown in Fig 1. Such results resemble those shown in Table 4, since baseline plasma folate concentrations were strongly related to multivitamin intake (see Table 2).
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, t test: T/T vs C/C.
On the basis of the findings shown in Table 4, we hypothesized that subjects with the T/T mutation may be more susceptible to elevated levels of tHcy at marginally low folate levels. To test this hypothesis, baseline levels of tHcy were plotted as a function of baseline folate levels (Fig 2). Levels of tHcy were similar in all subjects at high plasma levels of folate but increased at an accelerated rate (ie, with a steeper slope) at lower folate levels in MTHFR T677 homozygotes compared with C/T heterozygotes or C/C subjects.
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A stepwise regression analysis in all subjects indicated that about one third of the heterogeneity of the tHcy response to folate supplementation was attributed to initial plasma folate and tHcy levels, especially in nonusers of multivitamins (Table 5). However, these differences may be due in part to the unequal distribution of MTHFR genotypes in both groups, as shown in Table 2.
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Discussion |
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This study demonstrated that multivitamin users had lower baseline levels of tHcy than nonusers, in agreement with results previously reported by Brattstrom et al8 and Pietrzik et al.9 Moreover, multivitamin users had higher baseline concentration of plasma folate, P5'P, and vitamin B12. FA supplements lowered tHcy in nonusers of multivitamins, whereas the decreases of tHcy were minimal in multivitamin users, since, as indicated above, the relative tHcy changes were inversely proportional to the baseline folate and directly proportional to the baseline tHcy levels. However, the tHcy levels attained after folate supplementation in users of multivitamins were somewhat lower than those reached in nonusers of multivitamins, perhaps due to interactions with other vitamins, the longer duration of multivitamin intake, or factors not identified in this study. Nonetheless, it seems likely that FA is mainly responsible for the effects of multivitamins on tHcy, since decreases in tHcy levels were not observed in subjects ingesting a multivitamin lacking FA.13
Our data show that supplementary doses of 1 or 2 mg of FA decreased tHcy levels equally, regardless of sex, age, presence of CHD, BMI, smoking, or plasma creatinine concentration. Whether dosages higher than 2 mg/d or a longer-term observation would have greater effects needs to be established. Previous studies, including some that were also short term, showed similar tHcy reductions with 2.5 or 10 mg/d of FA in CHD patients,5 0.5 or 5.0 mg/d in subjects with tHcy<16 µmol/L,6 and 0.65 or 5 mg/d in hyperhomocyst(e)inemic individuals.7 Our results and the data analyzed by Boushey et al2 suggest that significant reduction of tHcy levels may be achieved by ingesting a supplement of about 400 µg of FA daily. Consequently, it may be considered to exclude from certain clinical trials participants who report current use of multivitamins on a regular basis.
The enzyme MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, thus transferring a methyl group to cobalamin, which in turn, donates a methyl group for the conversion of homocysteine to methionine. Kang et al14 15 16 reported the presence of a common homozygous thermolabile form of MTHFR in 5% of white controls and in 17% of CHD patients. The DNA mutation responsible for the heat-labile variant has been identified as a C-to-T mutation at nucleotide 677, which substitutes a valine for alanine at position 114 of the MTHFR protein.12 17 The frequency of the homozygous form (T/T) of this polymorphism was 12% in French Canadians17 and 12% to 15% in populations of European, Middle Eastern, and Japanese origin.18 The frequency of homozygotes for the T677 allele in 60 Dutch patients with arterial occlusive diseases was 15%, compared with 5.2% in 111 control subjects.19 However, such differences between CHD cases and control subjects were not confirmed by Deeb and Motulsky (unpublished observations), by Schwartz et al,20 or by Wilcken et al.21 In our series, tHcy was higher in subjects homozygous for the T677 allele, and T677 homozygotes were more prevalent in CHD patients than in non-CHD subjects (12.1% versus 7.8%, respectively). Whether the disparity with other reported series is due to differences in genetic pools or other undetermined factors needs further study.
Our findings demonstrated a significant negative correlation between tHcy and basal levels of folate, P5'P, and B12; the simultaneous intake of these vitamins in multivitamins may be involved in interactions that could partially account for these associations. Hopkins et al22 measured plasma tHcy, folate, and vitamins B6 and B12 in subjects with early familial CHD and in control subjects. Their data suggested a "possible genetic sensitivity" to the detrimental effects of low folate intake. The relationship between folate status, MTHFR polymorphism, and plasma tHcy has been established in the detailed study of Jacques et al.23 Our data suggest that basal levels of plasma vitamins and tHcy, as well as the effects of folate supplements on tHcy levels, are significantly influenced by multivitamin use. Moreover, subjects homozygous for the T677 MTHFR allele had larger decreases in plasma tHcy levels after FA supplementation, whereas the FA supplements induced smaller tHcy decreases in homozygotes for the C677 allele, especially in subjects with higher baseline folate levels.
It could be broadly surmised that individuals in whom tHcy levels are not lowered by FA supplementation may be more likely to lack the T677 MTHFR allele. In those subjects, additional treatment with other agents, such as pyridoxine, cobalamin, or betaine,7 24 25 may be advisable. Subjects homozygous for the T677 allele were more likely to have elevated levels of tHcy in the presence of low folate status (see Fig 2), as reported earlier,22 and they may have higher folate requirements to regulate tHcy, as proposed by Jacques et al.23 Our data suggest that decreases in tHcy associated with folate supplementation are related to prior intake of multivitamins, baseline tHcy, and folate plasma concentration. These factors may account for about one third of the heterogeneity of the response of tHcy to FA supplementation. Additionally, the response to folate supplementation is affected by the number of T677 alleles in the gene for MTHFR, and thus, subjects with the T/T genotype showed the most robust response to the tHcy-lowering effects of FA. It is likely that other factors not considered in our study may also be involved in that response. Further research is necessary to delineate those interactions to formulate a rational approach to the clinical management of patients at risk for arterial diseases.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was aided by grants from the Nohlgren/Menne Fund (Providence St Vincent Medical Center Foundation), from Merck Inc, and grant P51RR00163-34 from the National Institutes of Health. We are grateful to members of the cardiology section and to internists and family practice physicians of Providence St Vincent Medical Center for allowing us to conduct this study in their patients, to Liqun Wang for performing some of the MTHFR genotyping, and to Andrea Irvin-Jones for data management and editorial assistance.
Received April 23, 1996; accepted October 18, 1996.
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References |
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I. P Fohr, R. Prinz-Langenohl, A. Bronstrup, A. M Bohlmann, H. Nau, H. K Berthold, and K. Pietrzik 5,10-Methylenetetrahydrofolate reductase genotype determines the plasma homocysteine-lowering effect of supplementation with 5-methyltetrahydrofolate or folic acid in healthy young women Am. J. Clinical Nutrition, February 1, 2002; 75(2): 275 - 282. [Abstract] [Full Text] [PDF]
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 A. Rydlewicz, J.A. Simpson, R.J. Taylor, C.M. Bond, and M.H.N. Golden The effect of folic acid supplementation on plasma homocysteine in an elderly population QJM, January 1, 2002; 95(1): 27 - 35. [Abstract] [Full Text] [PDF]
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P. Madonna, V. de Stefano, A. Coppola, F. Cirillo, A. M. Cerbone, G. Orefice, and G. Di Minno Hyperhomocysteinemia and Other Inherited Prothrombotic Conditions in Young Adults With a History of Ischemic Stroke Stroke, January 1, 2002; 33(1): 51 - 56. [Abstract] [Full Text] [PDF]
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M.-L. Silaste, M. Rantala, M. Sampi, G. Alfthan, A. Aro, and Y. A. Kesaniemi Polymorphisms of Key Enzymes in Homocysteine Metabolism Affect Diet Responsiveness of Plasma Homocysteine in Healthy Women J. Nutr., October 1, 2001; 131(10): 2643 - 2647. [Abstract] [Full Text] [PDF]
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J. A. Tice, E. Ross, P. G. Coxson, I. Rosenberg, M. C. Weinstein, M. G. M. Hunink, P. A. Goldman, L. Williams, and L. Goldman Cost-effectiveness of Vitamin Therapy to Lower Plasma Homocysteine Levels for the Prevention of Coronary Heart Disease: Effect of Grain Fortification and Beyond JAMA, August 22, 2001; 286(8): 936 - 943. [Abstract] [Full Text] [PDF]
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 M. Weger, O. Stanger, H. Deutschmann, M. Simon, W. Renner, O. Schmut, J. Semmelrock, and A. Haas Hyperhomocyst(e)inaemia, but not MTHFR C677T mutation, as a risk factor for non-arteritic ischaemic optic neuropathy Br J Ophthalmol, July 1, 2001; 85(7): 803 - 806. [Abstract] [Full Text] [PDF]
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 M. Roest, Y. T. van der Schouw, D. E. Grobbee, M. J. Tempelman, P. G. de Groot, J. J. Sixma, and J. D. Banga Methylenetetrahydrofolate Reductase 677 C/T Genotype and Cardiovascular Disease Mortality in Postmenopausal Women Am. J. Epidemiol., April 1, 2001; 153(7): 673 - 679. [Abstract] [Full Text] [PDF]
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 E. Descombes, O. Boulat, L.-F. Bersier, and G. Fellay Difference in the homocysteine-lowering effect of folic acid in haemodialysis patients with and without occlusive vascular disease Nephrol. Dial. Transplant., March 1, 2001; 16(3): 585 - 589. [Abstract] [Full Text] [PDF]
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S.-M. Saw, J.-M. Yuan, C.-N. Ong, K. Arakawa, H.-P. Lee, G. A Coetzee, and M. C Yu Genetic, dietary, and other lifestyle determinants of plasma homocysteine concentrations in middle-aged and older Chinese men and women in Singapore Am. J. Clinical Nutrition, February 1, 2001; 73(2): 232 - 239. [Abstract] [Full Text] [PDF]
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 I. F. Godsland, J. R. Rosankiewicz, A. J. Proudler, and D. G. Johnston Plasma Total Homocysteine Concentrations Are Unrelated to Insulin Sensitivity and Components of the Metabolic Syndrome in Healthy Men J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 719 - 723. [Abstract] [Full Text]
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E. E Delvin, R. Rozen, A. Merouani, J. Genest Jr, and M. Lambert Influence of methylenetetrahydrofolate reductase genotype, age, vitamin B-12, and folate status on plasma homocysteine in children Am. J. Clinical Nutrition, December 1, 2000; 72(6): 1469 - 1473. [Abstract] [Full Text] [PDF]
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D. L. McKay, G. Perrone, H. Rasmussen, G. Dallal, and J. B. Blumberg Multivitamin/Mineral Supplementation Improves Plasma B-Vitamin Status and Homocysteine Concentration in Healthy Older Adults Consuming a Folate-Fortified Diet J. Nutr., December 1, 2000; 130(12): 3090 - 3096. [Abstract] [Full Text] [PDF]
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V. Shpichinetsky, I. Raz, Y. Friedlander, N. Goldschmidt, I. D. Wexler, A. Ben-Yehuda, and G. Friedman The Association between Two Common Mutations C677T and A1298C in Human Methylenetetrahydrofolate Reductase Gene and the Risk for Diabetic Nephropathy in Type II Diabetic Patients J. Nutr., October 1, 2000; 130(10): 2493 - 2497. [Abstract] [Full Text]
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P. M Ueland, H. Refsum, S. A. Beresford, and S. E. Vollset The controversy over homocysteine and cardiovascular risk Am. J. Clinical Nutrition, August 1, 2000; 72(2): 324 - 332. [Abstract] [Full Text] [PDF]
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M. R. Malinow, P. B. Duell, A. Irvin-Jones, B. M. Upson, and E. E. Graf Increased Plasma Homocyst(e)ine after Withdrawal of Ready-to-Eat Breakfast Cereal from the Diet: Prevention by Breakfast Cereal Providing 200 {micro}g Folic Acid J. Am. Coll. Nutr., August 1, 2000; 19(4): 452 - 457. [Abstract] [Full Text] [PDF]
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A. J. Levine, K. D. Siegmund, C. M. Ervin, A. Diep, E. R. Lee, H. D. Frankl, and R. W. Haile The Methylenetetrahydrofolate Reductase 677C{->}T Polymorphism and Distal Colorectal Adenoma Risk Cancer Epidemiol. Biomarkers Prev., July 1, 2000; 9(7): 657 - 663. [Abstract] [Full Text]
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 G. L. Booth, E. E.L. Wang, and with the Canadian Task Force on Preventive Health Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events Can. Med. Assoc. J., July 1, 2000; 163(1): 21 - 29. [Abstract] [Full Text] [PDF]
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L. J Riddell, A. Chisholm, S. Williams, and J. I Mann Dietary strategies for lowering homocysteine concentrations Am. J. Clinical Nutrition, June 1, 2000; 71(6): 1448 - 1454. [Abstract] [Full Text] [PDF]
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 G. SUNDER-PLASSMANN, M. FÖDINGER, H. BUCHMAYER, M. PAPAGIANNOPOULOS, J. WOJCIK, J. KLETZMAYR, B. ENZENBERGER, O. JANATA, W. C. WINKELMAYER, G. PAUL, et al. Effect of High Dose Folic Acid Therapy on Hyperhomocysteinemia in Hemodialysis Patients: Results of the Vienna Multicenter Study J. Am. Soc. Nephrol., June 1, 2000; 11(6): 1106 - 1116. [Abstract] [Full Text]
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C. M. Ulrich, E. Kampman, J. Bigler, S. M. Schwartz, C. Chen, R. Bostick, L. Fosdick, S. A. A. Beresford, Y. Yasui, and J. D. Potter Lack of Association between the C677T MTHFR Polymorphism and Colorectal Hyperplastic Polyps Cancer Epidemiol. Biomarkers Prev., April 1, 2000; 9(4): 427 - 433. [Abstract] [Full Text]
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S. E. Vollset, O. Nygard, H. Refsum, and P. M. Ueland Coffee and homocysteine1 Am. J. Clinical Nutrition, February 1, 2000; 71(2): 403 - 404. [Full Text] [PDF]
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 K. S. Woo, P. Chook, Y. I. Lolin, J. E. Sanderson, C. Metreweli, and D. S. Celermajer Folic acid improves arterial endothelial function in adults with hyperhomocystinemia J. Am. Coll. Cardiol., December 1, 1999; 34(7): 2002 - 2006. [Abstract] [Full Text] [PDF]
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 V. Fonseca, S. C. Guba, and L. M. Fink Hyperhomocysteinemia and the Endocrine System: Implications for Atherosclerosis and Thrombosis Endocr. Rev., October 1, 1999; 20(5): 738 - 759. [Abstract] [Full Text]
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C. M. Ulrich, E. Kampman, J. Bigler, S. M. Schwartz, C. Chen, R. Bostick, L. Fosdick, S. A. A. Beresford, Y. Yasui, and J. D. Potter Colorectal Adenomas and the C677T MTHFR Polymorphism: Evidence for Gene-Environment Interaction? Cancer Epidemiol. Biomarkers Prev., August 1, 1999; 8(8): 659 - 668. [Abstract] [Full Text]
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G. T Gerhard, M R. Malinow, T. G DeLoughery, A. J Evans, G. Sexton, S. L Connor, R. C Wander, and W. E Connor Higher total homocysteine concentrations and lower folate concentrations in premenopausal black women than in premenopausal white women Am. J. Clinical Nutrition, August 1, 1999; 70(2): 252 - 260. [Abstract] [Full Text] [PDF]
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 D. Gemmati, M. Previati, M. L. Serino, S. Moratelli, S. Guerra, S. Capitani, E. Forini, G. Ballerini, and G. L. Scapoli Low Folate Levels and Thermolabile Methylenetetrahydrofolate Reductase as Primary Determinant of Mild Hyperhomocystinemia in Normal and Thromboembolic Subjects Arterioscler Thromb Vasc Biol, July 1, 1999; 19(7): 1761 - 1767. [Abstract] [Full Text] [PDF]
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F. Nappo, N. De Rosa, R. Marfella, D. De Lucia, D. Ingrosso, A. F. Perna, B. Farzati, and D. Giugliano Impairment of Endothelial Functions by Acute Hyperhomocysteinemia and Reversal by Antioxidant Vitamins JAMA, June 9, 1999; 281(22): 2113 - 2118. [Abstract] [Full Text] [PDF]
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P B. Duell, M R. Malinow, J. V Woodside, I. S Young, J. W. Yarnell, D. McMaster, C. C Patterson, E. E McCrum, A. Evans, K F. Gey, et al. Effects of folic acid on homocysteine in persons classified by methylenetetrahydrofolate reductase genotype Am. J. Clinical Nutrition, June 1, 1999; 69(6): 1287 - 1289. [Full Text] [PDF]
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S. C. de Jong, C. D. A. Stehouwer, M. van den Berg, P. J. Kostense, D. Alders, C. Jakobs, G. Pals, and J. A. Rauwerda Determinants of Fasting and Post-Methionine Homocysteine Levels in Families Predisposed to Hyperhomocysteinemia and Premature Vascular Disease Arterioscler Thromb Vasc Biol, May 1, 1999; 19(5): 1316 - 1324. [Abstract] [Full Text] [PDF]
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 S L Tokgözoglu, M Alikasifoglu, I Ünsal, E Atalar, K Aytemir, N Özer, K Övünç, O Usal, S Kes, and E Tunçbilek Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate Heart, May 1, 1999; 81(5): 518 - 522. [Abstract] [Full Text]
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L. B. Bailey and J. F. Gregory III Polymorphisms of Methylenetetrahydrofolate Reductase and Other Enzymes: Metabolic Significance, Risks and Impact on Folate Requirement J. Nutr., May 1, 1999; 129(5): 919 - 922. [Abstract] [Full Text]
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 M. R. Malinow, A. G. Bostom, and R. M. Krauss Homocyst(e)ine, Diet, and Cardiovascular Diseases : A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association Circulation, January 12, 1999; 99(1): 178 - 182. [Full Text] [PDF]
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L. Brattstrom, D. E. L. Wilcken, J. Ohrvik, and L. Brudin Common Methylenetetrahydrofolate Reductase Gene Mutation Leads to Hyperhomocysteinemia but Not to Vascular Disease : The Result of a Meta-Analysis Circulation, December 8, 1998; 98(23): 2520 - 2526. [Abstract] [Full Text] [PDF]
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K. Demuth, N. Moatti, O. Hanon, M. O. Benoit, M. Safar, and X. Girerd Opposite Effects of Plasma Homocysteine and the Methylenetetrahydrofolate Reductase C677T Mutation on Carotid Artery Geometry in Asymptomatic Adults Arterioscler Thromb Vasc Biol, December 1, 1998; 18(12): 1838 - 1843. [Abstract] [Full Text] [PDF]
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J.-H. Yoo, C.-S. Chung, and S.-S. Kang Relation of Plasma Homocyst(e)ine to Cerebral Infarction and Cerebral Atherosclerosis Stroke, December 1, 1998; 29(12): 2478 - 2483. [Abstract] [Full Text] [PDF]
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 D. E.C. Cole, H. J. Ross, J. Evrovski, L. J. Langman, S. E.S. Miner, P. A. Daly, and P.-Y. Wong Correlation between total homocysteine and cyclosporine concentrations in cardiac transplant recipients Clin. Chem., November 1, 1998; 44(11): 2307 - 2312. [Abstract] [Full Text] [PDF]
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H. Morita, H. Kurihara, S.-i. Tsubaki, T. Sugiyama, C. Hamada, Y. Kurihara, T. Shindo, Y. Oh-hashi, K. Kitamura, and Y. Yazaki Methylenetetrahydrofolate Reductase Gene Polymorphism and Ischemic Stroke in Japanese Arterioscler Thromb Vasc Biol, September 1, 1998; 18(9): 1465 - 1469. [Abstract] [Full Text] [PDF]
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W. L.D.M. Nelen, H. J. Blom, C. M. G. Thomas, E. A. P. Steegers,, G. H. J. Boers, and T. K.A.B. Eskes Methylenetetrahydrofolate Reductase Polymorphism Affects the Change in Homocysteine and Folate Concentrations Resulting from Low Dose Folic Acid Supplementation in Women with Unexplained Recurrent Miscarriages J. Nutr., August 1, 1998; 128(8): 1336 - 1341. [Abstract] [Full Text]
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 D. Girelli, S. Friso, E. Trabetti, O. Olivieri, C. Russo, R. Pessotto, G. Faccini, P. F. Pignatti, A. Mazzucco, and R. Corrocher Methylenetetrahydrofolate Reductase C677T Mutation, Plasma Homocysteine, and Folate in Subjects From Northern Italy With or Without Angiographically Documented Severe Coronary Atherosclerotic Disease: Evidence for an Important Genetic-Environmental Interaction Blood, June 1, 1998; 91(11): 4158 - 4163. [Abstract] [Full Text] [PDF]
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 M. R. Malinow, P. B. Duell, D. L. Hess, P. H. Anderson, W. D. Kruger, B. E. Phillipson, R. A. Gluckman, P. C. Block, and B. M. Upson Reduction of Plasma Homocyst(e)ine Levels by Breakfast Cereal Fortified with Folic Acid in Patients with Coronary Heart Disease N. Engl. J. Med., April 9, 1998; 338(15): 1009 - 1015. [Abstract] [Full Text] [PDF]
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M. den Heijer, I. A. Brouwer, G. M. J. Bos, H. J. Blom, N. M. J. van der Put, A. P. Spaans, F. R. Rosendaal, C. M. G. Thomas, H. L. Haak, P. W. Wijermans, et al. Vitamin Supplementation Reduces Blood Homocysteine Levels : A Controlled Trial in Patients With Venous Thrombosis and Healthy Volunteers Arterioscler Thromb Vasc Biol, March 1, 1998; 18(3): 356 - 361. [Abstract] [Full Text] [PDF]
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G. S. Omenn, S. A. A. Beresford, and A. G. Motulsky Preventing Coronary Heart Disease : B Vitamins and Homocysteine Circulation, February 10, 1998; 97(5): 421 - 424. [Full Text] [PDF]
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 D. Thomas, A. Becker, and Y. Surdin-Kerjan Reverse Methionine Biosynthesis from S-Adenosylmethionine in Eukaryotic Cells J. Biol. Chem., December 22, 2000; 275(52): 40718 - 40724. [Abstract] [Full Text] [PDF]
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