(Circulation. 1996;93:7-9.)
© 1996 American Heart Association, Inc.
Articles |
Relation Between Folate Status, a Common Mutation in Methylenetetrahydrofolate Reductase, and Plasma Homocysteine Concentrations
From the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Mass (P.F.J., A.G.B., I.H.R., J.S.); the NHLBI Family Heart Study, University of Utah Cardiovascular Genetics Research Clinic, Salt Lake City (R.R.W.); the NHLBI Family Heart Study, Framingham, Mass, and Boston (Mass) University School of Medicine (R.C.E.); the NHLBI Family Heart Study Central Laboratory, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (J.H.E.); and the Departments of Human Genetics, Pediatrics, and Biology, McGill University, Montreal (Quebec) Children's Hospital (R.R.).
Correspondence to Rima Rozen, Montreal Children's Hospital, 2300 Tupper St, Montreal, Quebec, Canada H3H 1P3.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, the major carbon donor in remethylation of homocysteine to methionine. A common MTHFR mutation, an alanine-to-valine substitution, renders the enzyme thermolabile and may cause elevated plasma levels of the amino acid homocysteine.
Methods and Results To assess the potential interaction
between this mutation and vitamin coenzymes in homocysteine
metabolism, we screened 365 individuals from the NHLBI
Family Heart Study. Among individuals with lower plasma folate
concentrations (<15.4 nmol/L), those with the homozygous mutant
genotype had total fasting homocysteine levels that were 24%
greater (P<.05) than individuals with the normal
genotype. A difference between genotypes was not seen
among individuals with folate levels 
15.4 nmol/L.
Conclusions Individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations; folate supplementation may be necessary to prevent fasting hyperhomocysteinemia in such persons.
Key Words: enzymes • homocysteine • amino acids • metabolism • genetics
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Homocysteine is a sulfur amino acid whose metabolism is at the intersection of two metabolic pathways: remethylation and transsulfuration.1 In remethylation, the primary methyl donor for the vitamin B12-dependent conversion of homocysteine to methionine is 5-methyltetrahydrofolate, the principal circulating form of folate. 5-Methyltetrahydrofolate is synthesized from 5,10-methylenetetrahydrofolate by the enzyme MTHFR. In the transsulfuration pathway, homocysteine condenses with serine to form cystathionine in an irreversible reaction catalyzed by the PLP-containing enzyme CBS. These pathways can be disrupted by genetic defects in the two enzymes CBS and MTHFR or by deficiencies of folate, vitamin B12, and vitamin B6.
Because of the existence of a cellular homocysteine export mechanism, plasma normally contains a small amount of homocysteine, averaging 10 µmol/L.2 This export mechanism complements the catabolism of homocysteine to help maintain low intracellular concentrations of this potentially cytotoxic sulfur amino acid. In hyperhomocysteinemia, plasma homocysteine concentrations are elevated, indicating that homocysteine metabolism has in some way been disrupted. The more severe cases of hyperhomocysteinemia are primarily due to defects in the genes encoding CBS3 and MTHFR.4
A potential consequence of even moderate elevations of plasma
homocysteine may be an increased risk of occlusive vascular
disease.5 Accordingly, investigation of the determinants
of moderate hyperhomocysteinemia has intensified. Inadequate status of
nutritional coenzymes in homocysteine metabolism, at least
in the elderly, appears to be a major determinant of moderate
hyperhomocysteinemia.5 6 However, recent evidence
suggests
that common enzyme mutations may also be important determinants of
hyperhomocysteinemia. In 1988, Kang et al7 reported a
variant of MTHFR that was distinguishable from the normal enzyme by its
lower specific activity and its heat sensitivity and suggested that
this thermolabile variant was an inherited autosomal recessive trait
that is present in 
5% of the general population and 17% of
patients with coronary disease.8 Subsequently, one
of us (R.R.) and coworkers isolated the cDNA for human
MTHFR4 and demonstrated that thermolabile MTHFR is caused
by an alanine-to-valine (Ala-to-Val) missense
mutation.9 Twelve percent of French Canadians were shown
to have the homozygous mutant genotype for this polymorphic
variant.9
The impact of thermolabile MTHFR on hyperhomocysteinemia remains equivocal. Kang et al8 demonstrated that even though plasma homocysteine levels were higher among individuals with thermolabile MTHFR than among those with normal enzyme activity, many of those with the thermolabile enzyme did not have hyperhomocysteinemia. Furthermore, the hyperhomocysteinemia seen in the original study of Kang et al7 was associated with low plasma folate concentrations, and folate supplementation normalized the plasma homocysteine concentrations. These data suggested that folate status might play a crucial role in the development of hyperhomocysteinemia in individuals with the thermolabile defect.
To test the hypothesis that homocysteine concentrations in individuals with thermolabile MTHFR are dependent on folate status, we examined the influence of plasma folate concentration on the relation between the MTHFR thermolabile polymorphism and plasma homocysteine concentrations, using data from the NHLBI FHS.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Subjects
Subjects were participants in the NHLBI FHS. The FHS was established to evaluate genetic and nongenetic determinants of coronary heart disease in randomly sampled families and families known to be at high risk for coronary heart disease. Subject examinations began in February 1994 and are expected to be complete by January 1996. Two of the four sites participating in the FHS are involved in an ancillary homocysteine study, which is described in greater detail elsewhere.10 All persons at these sites undergoing the complete FHS phase II evaluation were invited to participate in the ancillary project, with the following exclusion criteria: age <25 or >69 years old, fasting for <10 hours, and lack of informed consent. This ancillary homocysteine study protocol was approved by the FHS Steering Committee and Safety Monitoring Board and the institutional review boards for Boston University School of Medicine, the University of Utah, and Tufts–New England Medical Center. These preliminary analyses are based on the initial 365 subjects enrolled in the ancillary homocysteine study.
Fasting Blood Collection
Immediately upon arriving, before
methionine loading, subjects
underwent fasting (>10 hours) phlebotomy. One 10-mL EDTA-containing
vacuum tube was obtained, and the plasma was promptly separated,
divided into aliquots, and stored at -70°C. DNA was purified by
a commercially available salt precipitation method (Puragene from
Gentra Systems, Inc).
Methionine Load Test
Methionine (100 mg/kg) was administered
in 200 mL of fruit juice
immediately after the fasting phlebotomy. Four hours after the
methionine load, a repeat plasma sample was obtained for homocysteine
determination.
Laboratory Determinations
As previously
described,6 total homocysteine in
plasma was determined by high-performance liquid
chromatography with fluorometric detection, plasma
folate by a 96-well plate microbial (Lactobacillus casei)
assay, plasma PLP by the tyrosine decarboxylase apoenzyme method, and
plasma vitamin B12 by a radioassay.
MTHFR Genotype Determination
The polymerase chain reaction
primers for amplification of the
MTHFR mutation have been described elsewhere.9 The primers
generate a 198-bp fragment. The MTHFR polymorphism, a C-to-T
substitution at bp 677, creates a HinfI recognition
sequence. If the mutation is present, HinfI digests the
198-bp fragment into a 175-bp and a 23-bp fragment. The fragments were
analyzed by polyacrylamide gel electrophoresis.
Statistical Methods
All plasma measures were positively
skewed, and we used
logarithmic transformations to normalize their distributions. Thus, all
means presented here are geometric means. To describe the
relationships between MTHFR thermolabile genotype and plasma
homocysteine and vitamin concentrations, we calculated the geometric
mean levels of these factors in individuals with normal (Ala/Ala),
heterozygous (Val/Ala), and homozygous (Val/Val) mutant
genotypes. We used ANOVA to test for differences between
genotypes and for interactions between genotype and
vitamin levels. Because age and sex adjustment had no influence on the
observed results, we present only the unadjusted data.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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We measured total fasting and post–methionine load homocysteine concentrations. Mean total fasting homocysteine concentrations were slightly greater for homozygotes of the MTHFR thermolabile mutation, but there was a significant interaction between genotype and folate status (Table
). Among those
with plasma folate levels below the sample median (15.4 nmol/L), the
mean fasting homocysteine concentration was 24% greater
(P<.05) for homozygotes with the thermolabile mutation than
for either the normal or heterozygous individuals. No association was
observed between genotype and fasting homocysteine
concentrations in those with plasma folate levels at or above the
median. Neither PLP nor vitamin B12 modified the
association between genotype and fasting homocysteine.
Post–methionine load total homocysteine concentration was
unrelated to MTHFR genotype (Table) irrespective of plasma
vitamin concentrations. Mean plasma vitamin concentrations were also
unrelated to genotype.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Our data qualify the role of thermolabile MTHFR as a determinant of fasting homocysteine levels, revealing an interaction between MTHFR thermolabile genotype and folate status. Individuals who are homozygotes for the MTHFR thermolabile mutation have elevated fasting homocysteine concentrations when plasma folate concentration is in the lower range but not when folate is high. We further demonstrate that thermolabile MTHFR genotype is not associated with the post–methionine load increase in plasma homocysteine, consistent with the hypothesis that post–methionine load hyperhomocysteinemia is due primarily to defects in the transsulfuration pathway.11
In conclusion, these findings indicate that individuals with thermolabile MTHFR may have a higher folate requirement for regulation of plasma homocysteine concentrations and, more importantly, suggest a therapeutic strategy (ie, folate supplementation) to prevent fasting hyperhomocysteinemia in such persons.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This project was funded in part with federal funds from the US Department of Agriculture, Agricultural Research Service under contract 53-3K06-01 and NHLBI contract N01-HC-25106 and by the Medical Research Council of Canada. The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture.
Received September 20, 1995; revision received October 23, 1995; accepted October 30, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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S. R. Davis, E. P. Quinlivan, K. P. Shelnutt, D. R. Maneval, H. Ghandour, A. Capdevila, B. S. Coats, C. Wagner, J. Selhub, L. B. Bailey, et al. The Methylenetetrahydrofolate Reductase 677C->T Polymorphism and Dietary Folate Restriction Affect Plasma One-Carbon Metabolites and Red Blood Cell Folate Concentrations and Distribution in Women J. Nutr., May 1, 2005; 135(5): 1040 - 1044. [Abstract] [Full Text] [PDF]
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S. R. Davis, E. P. Quinlivan, K. P. Shelnutt, H. Ghandour, A. Capdevila, B. S. Coats, C. Wagner, B. Shane, J. Selhub, L. B. Bailey, et al. Homocysteine Synthesis Is Elevated but Total Remethylation Is Unchanged by the Methylenetetrahydrofolate Reductase 677C->T Polymorphism and by Dietary Folate Restriction in Young Women J. Nutr., May 1, 2005; 135(5): 1045 - 1050. [Abstract] [Full Text] [PDF]
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 M. J. Beck and B. Berman Review of Thrombophilic States Clinical Pediatrics, April 1, 2005; 44(3): 193 - 199. [PDF]
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C. Papoutsakis, N. Yiannakouris, Y. Manios, E. Papaconstantinou, F. Magkos, K. H. Schulpis, A. Zampelas, and A. L. Matalas Plasma Homocysteine Concentrations in Greek Children Are Influenced by an Interaction between the Methylenetetrahydrofolate Reductase C677T Genotype and Folate Status J. Nutr., March 1, 2005; 135(3): 383 - 388. [Abstract] [Full Text] [PDF]
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 T. L.J. Kelly, O. R. Neaga, B. C. Schwahn, R. Rozen, and J. M. Trasler Infertility in 5,10-Methylenetetrahydrofolate Reductase (MTHFR)-Deficient Male Mice Is Partially Alleviated by Lifetime Dietary Betaine Supplementation Biol Reprod, March 1, 2005; 72(3): 667 - 677. [Abstract] [Full Text] [PDF]
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 S Najib and V Sanchez-Margalet Homocysteine thiolactone inhibits insulin-stimulated DNA and protein synthesis: possible role of mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3 (GSK-3) and p70 S6K phosphorylation J. Mol. Endocrinol., February 1, 2005; 34(1): 119 - 126. [Abstract] [Full Text] [PDF]
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 I. J. Kullo and C. M. Ballantyne Conditional Risk Factors for Atherosclerosis Mayo Clin. Proc., February 1, 2005; 80(2): 219 - 230. [Abstract] [PDF]
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 W. C. Winkelmayer, R. Kramar, G. C. Curhan, A. Chandraker, G. Endler, M. Fodinger, W. H. Horl, and G. Sunder-Plassmann Fasting Plasma Total Homocysteine Levels and Mortality and Allograft Loss in Kidney Transplant Recipients: A Prospective Study J. Am. Soc. Nephrol., January 1, 2005; 16(1): 255 - 260. [Abstract] [Full Text] [PDF]
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J. D. Vaughn, L. B. Bailey, K. P. Shelnutt, K. M. v.-C. Dunwoody, D. R. Maneval, S. R. Davis, E. P. Quinlivan, J. F. Gregory III, D. W. Theriaque, and G. P. A. Kauwell Methionine Synthase Reductase 66A->G Polymorphism Is Associated with Increased Plasma Homocysteine Concentration When Combined with the Homozygous Methylenetetrahydrofolate Reductase 677C->T Variant J. Nutr., November 1, 2004; 134(11): 2985 - 2990. [Abstract] [Full Text] [PDF]
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G. V Dedoussis, D. B Panagiotakos, C. Chrysohoou, C. Pitsavos, A. Zampelas, D. Choumerianou, and C. Stefanadis Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C->T mutation on homocysteine concentrations in healthy adults: the ATTICA Study Am. J. Clinical Nutrition, October 1, 2004; 80(4): 849 - 854. [Abstract] [Full Text] [PDF]
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S. A. Craig Betaine in human nutrition Am. J. Clinical Nutrition, September 1, 2004; 80(3): 539 - 549. [Abstract] [Full Text] [PDF]
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S. Narayanan, J. McConnell, J. Little, L. Sharp, C. J. Piyathilake, H. Powers, G. Basten, and S. J. Duthie Associations between Two Common Variants C677T and A1298C in the Methylenetetrahydrofolate Reductase Gene and Measures of Folate Metabolism and DNA Stability (Strand Breaks, Misincorporated Uracil, and DNA Methylation Status) in Human Lymphocytes In vivo Cancer Epidemiol. Biomarkers Prev., September 1, 2004; 13(9): 1436 - 1443. [Abstract] [Full Text] [PDF]
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 T. A. Manolio, E. Boerwinkle, C. J. O'Donnell, and A. F. Wilson Genetics of Ultrasonographic Carotid Atherosclerosis Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1567 - 1577. [Abstract] [Full Text] [PDF]
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H. Chen, S. M. Zhang, M. A. Schwarzschild, M. A. Hernan, G. Logroscino, W. C. Willett, and A. Ascherio Folate Intake and Risk of Parkinson's Disease Am. J. Epidemiol., August 15, 2004; 160(4): 368 - 375. [Abstract] [Full Text] [PDF]
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M. Terzolo, B. Allasino, S. Bosio, E. Brusa, F. Daffara, M. Ventura, E. Aroasio, G. Sacchetto, G. Reimondo, A. Angeli, et al. Hyperhomocysteinemia in Patients with Cushing's Syndrome J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3745 - 3751. [Abstract] [Full Text] [PDF]
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C. Cantu, E. Alonso, A. Jara, L. Martinez, C. Rios, M. d. l. A. Fernandez, I. Garcia, and F. Barinagarrementeria Hyperhomocysteinemia, Low Folate and Vitamin B12 Concentrations, and Methylene Tetrahydrofolate Reductase Mutation in Cerebral Venous Thrombosis Stroke, August 1, 2004; 35(8): 1790 - 1794. [Abstract] [Full Text] [PDF]
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C. Chrysohoou, D. B Panagiotakos, C. Pitsavos, A. Zeimbekis, A. Zampelas, L. Papademetriou, C. Masoura, and C. Stefanadis The associations between smoking, physical activity, dietary habits and plasma homocysteine levels in cardiovascular disease-free people: the 'ATTICA' study Vascular Medicine, May 1, 2004; 9(2): 117 - 123. [Abstract] [PDF]
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M. E. Martinez, S. M Henning, and D. S Alberts Folate and colorectal neoplasia: relation between plasma and dietary markers of folate and adenoma recurrence Am. J. Clinical Nutrition, April 1, 2004; 79(4): 691 - 697. [Abstract] [Full Text] [PDF]
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 J. H. Townsend, S. R. Davis, A. D. Mackey, and J. F. Gregory III Folate deprivation reduces homocysteine remethylation in a human intestinal epithelial cell culture model: role of serine in one-carbon donation Am J Physiol Gastrointest Liver Physiol, April 1, 2004; 286(4): G588 - G595. [Abstract] [Full Text] [PDF]
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A. M. Devlin, E. Arning, T. Bottiglieri, F. M. Faraci, R. Rozen, and S. R. Lentz Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice Blood, April 1, 2004; 103(7): 2624 - 2629. [Abstract] [Full Text] [PDF]
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L. Sharp and J. Little Polymorphisms in Genes Involved in Folate Metabolism and Colorectal Neoplasia: A HuGE Review Am. J. Epidemiol., March 1, 2004; 159(5): 423 - 443. [Abstract] [Full Text] [PDF]
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M. J. Shrubsole, Y.-T. Gao, Q. Cai, X. O. Shu, Q. Dai, J. R. Hebert, F. Jin, and W. Zheng MTHFR Polymorphisms, Dietary Folate Intake, and Breast Cancer Risk: Results from the Shanghai Breast Cancer Study Cancer Epidemiol. Biomarkers Prev., February 1, 2004; 13(2): 190 - 196. [Abstract] [Full Text] [PDF]
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 S. Palomba, T. Russo, F. Orio Jr, A. Sammartino, F. M. Sbano, C. Nappi, A. Colao, P. Mastrantonio, G. Lombardi, and F. Zullo Lipid, glucose and homocysteine metabolism in women treated with a GnRH agonist with or without raloxifene Hum. Reprod., February 1, 2004; 19(2): 415 - 421. [Abstract] [Full Text] [PDF]
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B. Voetsch and J. Loscalzo Genetic Determinants of Arterial Thrombosis Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 216 - 229. [Abstract] [Full Text]
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 S. R. Davis, P. W. Stacpoole, J. Williamson, L. S. Kick, E. P. Quinlivan, B. S. Coats, B. Shane, L. B. Bailey, and J. F. Gregory III Tracer-derived total and folate-dependent homocysteine remethylation and synthesis rates in humans indicate that serine is the main one-carbon donor Am J Physiol Endocrinol Metab, February 1, 2004; 286(2): E272 - E279. [Abstract] [Full Text] [PDF]
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K.-J. Sohn, R. Croxford, Z. Yates, M. Lucock, and Y.-I. Kim Effect of the Methylenetetrahydrofolate Reductase C677T Polymorphism on Chemosensitivity of Colon and Breast Cancer Cells to 5-Fluorouracil and Methotrexate J Natl Cancer Inst, January 21, 2004; 96(2): 134 - 144. [Abstract] [Full Text] [PDF]
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 M. R Amorim, E. E Castilla, and I. M Orioli Is there a familial link between Down's syndrome and neural tube defects? Population and familial survey BMJ, January 10, 2004; 328(7431): 84. [Abstract] [Full Text] [PDF]
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H. Refsum, A. D. Smith, P. M. Ueland, E. Nexo, R. Clarke, J. McPartlin, C. Johnston, F. Engbaek, J. Schneede, C. McPartlin, et al. Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion Clin. Chem., January 1, 2004; 50(1): 3 - 32. [Abstract] [Full Text] [PDF]
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 A. Hassan, B. J. Hunt, M. O'Sullivan, R. Bell, R. D'Souza, S. Jeffery, J. M. Bamford, and H. S. Markus Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction Brain, January 1, 2004; 127(1): 212 - 219. [Abstract] [Full Text] [PDF]
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M. Krajinovic, S. Lamothe, D. Labuda, E. Lemieux-Blanchard, Y. Theoret, A. Moghrabi, and D. Sinnett Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia Blood, January 1, 2004; 103(1): 252 - 257. [Abstract] [Full Text] [PDF]
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W. Koch, G. Ndrepepa, J. Mehilli, S. Braun, M. Burghartz, H. Lengnick, K. Kolling, A. Schomig, and A. Kastrati Homocysteine Status and Polymorphisms of Methylenetetrahydrofolate Reductase Are Not Associated With Restenosis After Stenting in Coronary Arteries Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2229 - 2234. [Abstract] [Full Text] [PDF]
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L. D. Spotila, P. F. Jacques, P. B. Berger, K. V. Ballman, R. C. Ellison, and R. Rozen Age Dependence of the Influence of Methylenetetrahydrofolate Reductase Genotype on Plasma Homocysteine Level Am. J. Epidemiol., November 1, 2003; 158(9): 871 - 877. [Abstract] [Full Text] [PDF]
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G. T. Russo, S. Friso, P. F. Jacques, G. Rogers, D. Cucinotta, P. W. F. Wilson, J. M. Ordovas, I. H. Rosenberg, and J. Selhub Age and Gender Affect the Relation between Methylenetetrahydrofolate Reductase C677T Genotype and Fasting Plasma Homocysteine Concentrations in the Framingham Offspring Study Cohort J. Nutr., November 1, 2003; 133(11): 3416 - 3421. [Abstract] [Full Text] [PDF]
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L. B. Bailey Folate, Methyl-Related Nutrients, Alcohol, and the MTHFR 677C->T Polymorphism Affect Cancer Risk: Intake Recommendations J. Nutr., November 1, 2003; 133(11): 3748S - 3753. [Abstract] [Full Text] [PDF]
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G. M. Shaw, H. Zhu, E. J. Lammer, W. Yang, and R. H. Finnell Genetic Variation of Infant Reduced Folate Carrier (A80G) and Risk of Orofacial and Conotruncal Heart Defects Am. J. Epidemiol., October 15, 2003; 158(8): 747 - 752. [Abstract] [Full Text] [PDF]
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H. Zetterberg, A. Zafiropoulos, D. A. Spandidos, L. Rymo, and K. Blennow Gene-gene interaction between fetal MTHFR 677C>T and transcobalamin 776C>G polymorphisms in human spontaneous abortion Hum. Reprod., September 1, 2003; 18(9): 1948 - 1950. [Abstract] [Full Text] [PDF]
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L. Lathrop Stern, B. Shane, P. J. Bagley, M. Nadeau, V. Shih, and J. Selhub Combined Marginal Folate and Riboflavin Status Affect Homocysteine Methylation in Cultured Immortalized Lymphocytes from Persons Homozygous for the MTHFR C677T Mutation J. Nutr., September 1, 2003; 133(9): 2716 - 2720. [Abstract] [Full Text] [PDF]
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Z. Li, L. Sun, H. Zhang, Y. Liao, D. Wang, B. Zhao, Z. Zhu, J. Zhao, A. Ma, Y. Han, et al. Elevated Plasma Homocysteine Was Associated With Hemorrhagic and Ischemic Stroke, but Methylenetetrahydrofolate Reductase Gene C677T Polymorphism Was a Risk Factor for Thrombotic Stroke: A Multicenter Case-Control Study in China Stroke, September 1, 2003; 34(9): 2085 - 2090. [Abstract] [Full Text] [PDF]
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N. Inamoto, T. Katsuya, Y. Kokubo, T. Mannami, T. Asai, S. Baba, J. Ogata, H. Tomoike, and T. Ogihara Association of Methylenetetrahydrofolate Reductase Gene Polymorphism With Carotid Atherosclerosis Depending on Smoking Status in a Japanese General Population Stroke, July 1, 2003; 34(7): 1628 - 1633. [Abstract] [Full Text] [PDF]
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K. S. Brown, L. A.J. Kluijtmans, I. S. Young, J. Woodside, J. W.G. Yarnell, D. McMaster, L. Murray, A. E. Evans, C. A. Boreham, H. McNulty, et al. Genetic Evidence That Nitric Oxide Modulates Homocysteine: The NOS3 894TT Genotype Is a Risk Factor for Hyperhomocystenemia Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1014 - 1020. [Abstract] [Full Text] [PDF]
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C. L. Guinotte, M. G. Burns, J. A. Axume, H. Hata, T. F. Urrutia, A. Alamilla, D. McCabe, A. Singgih, E. A. Cogger, and M. A. Caudill Methylenetetrahydrofolate Reductase 677C->T Variant Modulates Folate Status Response to Controlled Folate Intakes in Young Women J. Nutr., May 1, 2003; 133(5): 1272 - 1280. [Abstract] [Full Text] [PDF]
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D. Girelli, N. Martinelli, F. Pizzolo, S. Friso, O. Olivieri, C. Stranieri, E. Trabetti, G. Faccini, E. Tinazzi, P. F. Pignatti, et al. The Interaction between MTHFR 677 C->T Genotype and Folate Status Is a Determinant of Coronary Atherosclerosis Risk J. Nutr., May 1, 2003; 133(5): 1281 - 1285. [Abstract] [Full Text] [PDF]
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V. Ganji and M. R Kafai Demographic, health, lifestyle, and blood vitamin determinants of serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey, 1988-1994 Am. J. Clinical Nutrition, April 1, 2003; 77(4): 826 - 833. [Abstract] [Full Text] [PDF]
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R. Castro, I. Rivera, P. Ravasco, C. Jakobs, H.J. Blom, M.E. Camilo, and I.T. de Almeida 5,10-Methylenetetrahydrofolate reductase 677C->T and 1298A->C mutations are genetic determinants of elevated homocysteine QJM, April 1, 2003; 96(4): 297 - 303. [Abstract] [Full Text] [PDF]
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A. de Bree, W. M. Verschuren, A.-L. Bjorke-Monsen, N. M. van der Put, S. G Heil, F. J. Trijbels, and H. J Blom Effect of the methylenetetrahydrofolate reductase 677C->T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample Am. J. Clinical Nutrition, March 1, 2003; 77(3): 687 - 693. [Abstract] [Full Text] [PDF]
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J. B. Mason Biomarkers of Nutrient Exposure and Status in One-Carbon (Methyl) Metabolism J. Nutr., March 1, 2003; 133(3): 941S - 947. [Abstract] [Full Text] [PDF]
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F. Orio Jr., S. Palomba, S. Di Biase, A. Colao, L. Tauchmanova, S. Savastano, D. Labella, T. Russo, F. Zullo, and G. Lombardi Homocysteine Levels and C677T Polymorphism of Methylenetetrahydrofolate Reductase in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 673 - 679. [Abstract] [Full Text] [PDF]
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