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(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

Paul F. Jacques, ScD; Andrew G. Bostom, MD, MS; Roger R. Williams, MD; R. Curtis Ellison, MD, MS; John H. Eckfeldt, MD, PhD; Irwin H. Rosenberg, MD; Jacob Selhub, PhD; Rima Rozen, PhD

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.


*    Abstract
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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


*    Introduction
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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 {approx}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.


*    Methods
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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.


*    Results
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*Results
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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 (TableDown). 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 (TableDown) irrespective of plasma vitamin concentrations. Mean plasma vitamin concentrations were also unrelated to genotype.


View this table:
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Table 1. Total Plasma Homocysteine by MTHFR Genotype


*    Discussion
up arrowTop
up arrowAbstract
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*Discussion
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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.


*    Selected Abbreviations and Acronyms
 
CBS = cystathionine ß-synthase
FHS = NHLBI Family Heart Study
MTHFR = methylenetetrahydrofolate reductase
PLP = pyridoxal-5'-phosphate


*    Acknowledgments
 
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.


*    References
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up arrowAbstract
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*References
 

  1. Selhub J, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr. 1991;55:131-138. [Abstract/Free Full Text]
  2. Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH. Total homocysteine in plasma or serum: methods and applications. Clin Chem. 1993;39:1764-1773. [Abstract]
  3. Kraus JP. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis. 1994;17:383-390. [Medline] [Order article via Infotrieve]
  4. Goyette P, Sumner JS, Milos R, Duncan MV, Rosenblatt DS, Matthews RG, Rozen R. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet. 1994;7:195-200. [Medline] [Order article via Infotrieve]
  5. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049-1057. [Abstract]
  6. Selhub J, Jacques PF, Wilson PWF, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in the elderly. JAMA. 1993;270:2693-2698. [Abstract]
  7. Kang S-S, Zhou J, Wong PWK, Kowalisyn J, Strokosch G. Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet. 1988;43:414-421. [Medline] [Order article via Infotrieve]
  8. Kang S-S, Wong PWK, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet. 1991;48:536-545. [Medline] [Order article via Infotrieve]
  9. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuvel L, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111-113. [Medline] [Order article via Infotrieve]
  10. Bostom AG, Jacques PF, Nadeau MR, Williams RR, Ellison RC, Selhub J. Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis. 1995;116:147-151. [Medline] [Order article via Infotrieve]
  11. Miller JW, Nadeau MR, Smith D, Selhub J. Vitamin B6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr. 1994;59:1033-1039.[Abstract/Free Full Text]



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Nutr Clin PractHome page
G. P. A. Kauwell
Emerging Concepts in Nutrigenomics: A Preview of What Is to Come
Nutr Clin Pract, February 1, 2005; 20(1): 75 - 87.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
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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MutagenesisHome page
B. Smolkova, M. Dusinska, K. Raslova, M. Barancokova, A. Kazimirova, A. Horska, V. Spustova, and A. Collins
Folate levels determine effect of antioxidant supplementation on micronuclei in subjects with cardiovascular risk
Mutagenesis, November 1, 2004; 19(6): 469 - 476.
[Abstract] [Full Text] [PDF]


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J. Nutr.Home page
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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Am. J. Clin. Nutr.Home page
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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Clin. Chem.Home page
H. Refsum, A. W. Grindflek, P. M. Ueland, A. Fredriksen, K. Meyer, A. Ulvik, A. B. Guttormsen, O. E. Iversen, J. Schneede, and B. F. Kase
Screening for Serum Total Homocysteine in Newborn Children
Clin. Chem., October 1, 2004; 50(10): 1769 - 1784.
[Abstract] [Full Text] [PDF]