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Homocysteine as a risk factor for cardiovascular and related disease: nutritional implications

Published online by Cambridge University Press:  14 December 2007

Donald G. Weir  and
John M. Scott
Donald G. Weir
Affiliation:
Department of Clinical Medicine, Trinity College, Dublin
John M. Scott
Affiliation:
Department of Biochemistry, Trinity College, Dublin
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Abstract

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The objectives were firstly to assess the evidence that homocysteine is a significant and independent risk factor for vascular disease with special reference to cardiovascular disease, and secondly to evaluate the evidence that a food staple fortified with folic acid will reduce this problem on a population basis.

The structure of plasma homocysteine (tHcy) is described. Homocysteine, a highly reactive compound, is synthesized from the amino acid, methionine, and is metabolized by two pathways, the catabolic transsulphuration route via cystathionine β-synthase (EC 4.2.1.22) and the remethylation path using 5-methyltetrahy-drofolate polyglutamate, the product of 5,10-methylenetetrahydrofolate reductase (MTHFR; EC 1.1.1.171), via the cobalamin dependent enzyme, methionine synthase (MS; EC 2.1.1.13).

The mechanisms whereby hyper-tHcy is produced include both increased rates of synthesis and decreased metabolism. The latter may occur owing to nutritional deficiency of the vitamin cofactors which are necessary for the normal function of the metabolic enzymes. In particular, folate is required for methylene reductase, pyridoxal phosphate for cystathionine synthase and cobalamin for methionine synthase. When these vitamins are deficient hyper-tHcy is induced and this occurs especially in the elderly. Alternatively, a variant form of methylene reductase has recently been described which occurs in nearly 10% of the normal population. This variant is associated with hyper-tHcy, especially in situations associated with a low folate nutritional status.

Meta-analysis of both retrospective case-control studies, nested prospective case-control surveys and a secondary trial of mortality in postmyocardial infarct patients have shown that the association of hyper-tHcy with vascular disease is beyond doubt. This has been further supported by direct assessments of the degree of vascular disease in the carotid brachial and aortic arteries in relation to tHcy levels. Furthermore, treatment with a cocktail of the vitamin cofactors has produced lowering of tHcy levels and regression of the vascular disease in the carotid arteries of affected individuals.

Suggested pathogenic mechanisms in vascular disease induced by hyper-tHcy include vascular endothelial cell dysfunction, smooth muscle proliferation and derangements of normal intravascular regulation mechanisms. A variety of clinical conditions are known to be associated with a high incidence of thromboembolic complications. Some of these are associated with hyper-tHcy.

Low physiological doses of folic acid, as well as pharmocological doses, lower tHcy. However, because of the poor bioavailability of food folate (50%) and the considerable chemical instability of the naturally occurring reduced forms of folate, in most people it would require unacceptably high consumption of green vegetables to accomplish the necessary increase in intracellular folate and reduction in tHcy. Accordingly, folic acid, the nonreduced synthetic form of the vitamin, which is 100% bioavailable and chemically extremely stable, should be added to a food staple such as flour to ensure maximum protection for most of the population.

Type
Research Article
Information
Nutrition Research Reviews , Volume 11 , Issue 2 , December 1998 , pp. 311 - 338
Copyright
Copyright © The Nutrition Society 1998

References

Adams, M., Smith, P.D., Martin, D., Thompson, J.R., Lodwick, D. # Samani, N.J. (1996). Genetic analysis of thermolabile methylenetetrahydrofolate reductase as a risk factor for myocardial infarction. QJM: Monthly Journal of the Association of Physicians 89, 437–444.Google Scholar
Alfthan, G., Aro, A. # Gey, K.F. (1997). Plasma homocysteine and cardiovascular disease mortality. Lancet 349, 397.CrossRefGoogle ScholarPubMed
Alfthan, G., Pakkanen, J., Jaubirmen, M. et al. (1994). Relation of serum homocysteine and lipoprotein(a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 106, 9–16.Google Scholar
Allen, R.H., Stabler, S.P., Savage, D.G. # Lindenbaum, J. (1993). Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB Journal 7, 1344–1353.CrossRefGoogle ScholarPubMed
Andersson, A., Brattström, L., Israelsson, B., Isaksson, A., Hamfelt, A. # Hultberg, B. (1992 a). Plasma homocysteine before and after methionine loading with regard to age, gender and menopausal status. European Journal of Clinical Investigation 22, 79–87.Google Scholar
Andersson, A., Hultberg, B., Brattström, L. # Isaksson, A. (1992 b). Decreased serum homocysteine in pregnancy. European Journal of Clinical Chemistry # Clinical Biochemistry 30, 377–379.Google Scholar
Andus, T., Mollens, C., Geissler, A., Vogl, D., Gross, V., Schmitz, G., Henna, W. # Scholmenick, J. (1996). Elevated homocysteine concentrations in sera of patients with inflammatory bowel disease. Gastroenterology 110, A855(i).Google Scholar
Araki, A. # Sako, Y. (1987). Determination of free and total homocysteine in human plasma by high performance liquid chromatography with fluorescence detection. Journal of Chromatography: Biomedical Applications 422, 43–52.Google Scholar
Arnadottir, M., Hultberg, B., Nilsson-Ehle, P. # Thysell, H. (1996). The effect of reduced glomerular filtration rate on plasma total homocysteine concentration. Scandinavian Journal of Clinical Laboratory Investigation 56, 41–46.Google Scholar
Arnesen, E., Refsum, H., Bonaa, K.H., Ueland, P.M., Forde, O.H. # Nordrehaug, J.E. (1995). Serum total homocysteine and coronary heart disease. International Journal of Epidemiology 24, 704–709.Google Scholar
Aronson, D.C., Onkenhout, W., Raben, A.M.T.J., Oudenhoven, L.F.I.J., Brommer, E.J.P. # van Bockel, J.H. (1994). Impaired homocysteine metabolism: a risk factor in young adults with atherosclerotic arterial occlusive disease of the leg. British Journal of Surgery 81, 1114–1118.Google Scholar
Bachmann, J., Tepel, M., Raidt, H., Riezler, R., Graefe, U., Langer, K. # Zidek, W. (1995). Hyperhomocysteinemia and the risk for vascular disease in hemodialysis patients. Journal of the American Society of Nephrology 6, 121–125.Google Scholar
Blakley, R.L. (1969). The Biochemistry of Folic Acid and Related Pteridines (Frontiers in Biology, vol. 13). Amsterdam: North Holland.Google Scholar
Boers, G.H.J., Smals, A.G., Trijbels, F.J., Leermakers, A.I. # Kloppenborg, P.W. (1983). Unique efficiency of methionine metabolism in premenopausal women may protect against vascular disease in the reproductive years. Journal of Clinical Investigation 72, 1971–1976.Google Scholar
Boers, G.H.J., Smals, A.G.H., Trijbels, F.J.M., Fowler, B., Bakkeren, J.A.J.M., Schoonderwaldt, H.C., Kleijer, W.J. # Kloppenborg, P.W.C. (1985). Heterozygosity for homocysteinuria in premature peripheral and cerebral occlusive arterial disease. New England Journal of Medicine 313, 709–715.CrossRefGoogle Scholar
Bostom, A.G., Brosnan, J.T., Hall, B., Nadeau, M.R. # Selhub, J. (1995). Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis 116, 59–62.Google Scholar
Bostom, A.G., Shemin, D., Lapane, K.L., Nadeau, M.R., Sutherland, P., Chan, J., Rozen, R., Yoburn, D., Jacques, P.F., Selhub, J. # Rosenberg, I.H. (1996 a). Folate status is the major determinant of fasting total plasma homocysteine levels in maintenance dialysis patients. Atherosclerosis 123, 193–202.Google Scholar
Bostom, A.G., Shemin, D., Lapane, K.L., Sutherland, P., Nadeau, M.R., Wilson, P.W., Yobam, D., Bausserman, L., Tofler, G., Jacques, P.F., Selhub, J. # Rosenberg, I.H. (1996 b). Hyperhomocysteinaemia, hyperfibrinogenaemia and lipoprotein (a) excess in maintenance dialysis patients: a matched case-control study. Atherosclerosis 125, 91–101.Google Scholar
Boushey, C.J., Beresford, S.A.A., Omenn, G.S. # Motulsky, A.G. (1995). A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intake. JAMA: Journal of the American Medical Association 274, 1049–1057.Google Scholar
Brattström, L., Englund, E. # Brun, A. (1987). Does Down syndrome support homocysteine theory of arteriosclerosis? Lancet I, 391–392.Google Scholar
Brattström, L.E., Hardebo, J.E. # Hultberg, B.L. (1984). Moderate homocysteinemia—a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke 15, 1012–1016.Google Scholar
Brattström, L.E., Hultberg, B.L. # Hardebo, J.E. (1985). Folic acid responsive post-menopausal homocysteinemia. Metabolism 34, 1073–1077.Google Scholar
Brattström, L.E., Israelsson, B., Jeppsson, J.O. # Hultberg, B.L. (1988). Folic acid—an innocuous means to reduce plasma homocysteine. Scandinavian Journal of Clinical and Laboratory Investigation 48, 215–221.Google Scholar
Brattström, L., Israelsson, B., Norring, B., Bergqvist, D., Thörne, J., Hultberg, B. # Hamfelt, A. (1990). Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease: effects of pyrodoxine and folic acid treatment. Atherosclerosis 81, 51–60.Google Scholar
Brattström, L., Israelsson, B., Tengborn, L., # Hultberg, B. (1989). Homocysteine, factor VII and antithrombin III in subjects with different gene dosage of cystathionine-β-synthase. Journal of Inherited Metabolic Disease 12, 475–482.Google Scholar
Brattström, L., Lindgren, A., Israelsson, B., Andersson, A. # Hultberg, B. (1994). Homocysteine and cysteine: determinants of plasma levels in middle-aged and elderly subjects. Journal of Internal Medicine 236, 633–641.Google Scholar
Brattström, L., Lindgren, A., Israelsson, B., Malinow, M.R., Norrving, B., Upson, B. # Hamfelt, A. (1992). Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors. European Journal of Clinical Investigation 22, 214–221.Google Scholar
Carson, N.A.J. # Neill, D.W. (1962). Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Archives of Disease in Childhood 37, 505–513.Google Scholar
Chadefaux, B., Ceballos, I., Hamet, M., Coude, M., Poissonnier, M., Kamoun, P. # Allard, D. (1988). Is absence of atheroma in Down syndrome due to decreased homocysteine levels? Lancet 2, 741.Google Scholar
Chambers, J.C., McGregor, A., Jean-Marie, J. # Koower, J.S. (1998). Acute hyperhomocysteinaemia and endothelial dysfunction. Lancet 351, 36–37.Google Scholar
Chasan-Taber, L., Selhub, J., Rosenberg, I.H., Malinow, M.R., Terry, P., Tishler, P.V., Willet, W., Hennekens, C.H. # Stampfer, M.J. (1996). A prospective study of folate and vitamin B6 and risk of myocardial infarction in US physicians. Journal of the American College of Nutrition 15, 136–143.Google Scholar
Christensen, B., Frosst, P., Lussier-Cacan, S., Selhub, J., Goyette, P., Rosenblatt, D., Genest, J. # Rozen, R. (1997). Correlation of a common mutation in the methylene tetrahydrofolate reductase (MTHFR) gene with plasma homocysteine in patients with premature coronary artery disease. Arteriosclerosis, Thrombosis and Vascular Biology 17, 569–571.Google Scholar
Corrales, F., Gimenez, A., Alvarez, L., Caballeria, J., Pajares, M.A., Andreu, H., Pares, A., Mato, J.M. # Rodes, J. (1992). S-adenosylmethionine treatment prevents carbon tetrachloride-induced S-adenosylmethionine synthetase inactivation and attenuates liver injury. Hepatology 16, 1022–1027.Google Scholar
Corrales, F., Ochoa, P., Rivas, C., Martin-Lomas, M., Mato, J.M. # Pajares, M.A. (1991). Inhibition of glutathione synthesis in the liver leads to S-adenosyl-L-methionine synthetase reduction. Hepatology 14, 528–533.Google Scholar
Cronin, C.C., McPartlin, J.M., Barry, D.G., Ferris, B., Scott, J.M. # Weir, D.G. (1996). Plasma total homocyst(e)ine concentration and micro-vascular complications in insulin-dependent (Type 1) diabetes mellitus. Diabetic Medicine 13, 51.Google Scholar
Cuskelly, G.J., McNulty, H. # Scott, J.M. (1996). Effect of increasing dietary folate on red cell folate: implications for prevention of neural tube defects. Lancet 347, 657–659.Google Scholar
Daly, L.E., Kirke, P.N., Molloy, A., Weir, D.G. # Scott, J.M. (1995). Folate levels and neural tube defects. Implications for prevention. JAMA: Journal of the American Medical Association 274, 1698–1702.Google Scholar
Daly, S., Mills, J.L., Molloy, A.M., Conley, M., Lee, Y.J., Kirke, P.N., Weir, D.G. # Scott, J.M. (1997). Minimum effective dose of folic acid for food fortification to prevent neural-tube defects. Lancet 350, 1666–1669.Google Scholar
D'Angelo, A. # Selhub, J. (1997). Homocysteine and thrombotic disease. Blood 90, 1–11.Google Scholar
De la Haba, G. # Cantoni, G.L. (1959). The enzymatic synthesis of S-adenosyl-L-homocysteine from adenosine and homocysteine. Journal of Biological Chemistry 234, 603–608.Google Scholar
Delport, R., Ubbink, J.B., Vermaak, W.J.H., Rossouw, H., Becker, P.J. # Joubert, J. (1997). Hyperhomocysteinaemia in black patients with cerebral thrombosis. QJM: Monthly Journal of the Association of Physicians 90, 635–639.Google Scholar
den Heijer, M.D., Koster, T., Blom, H.J., Bos, G.M.J., Briet, E., Reitsma, P.H., Van den Broucke, J.P. # Rosendaal, F.R. (1996). Hyperhomocysteinemia as a risk factor for deep vein thrombosis. New England Journal of Medicine 334, 759–762.Google Scholar
Department of Health (1991). Dietary Reference Values for Food and Energy and Nutrients for the United Kingdom (Report on Health and Social Subjects no. 41). London: HMSO.Google Scholar
Dennis, V.W. # Robinson, K. (1996). Homocysteinaemia and vascular disease in end stage renal disease. Kidney International Suppl. 57, S11–17.Google Scholar
Drummond, J.T. # Matthews, R.G. (1994). Nitrous oxide inactivation of cobalamin-dependent methionine synthase from Escherichia coli: characterization of the damage to the enzyme and prosthetic group. Biochemistry 33, 3742–3750.Google Scholar
Dudman, N.P.B., Wilcken, D.E.L., Wang, J., Lynch, J.F., Macey, D. # Lundberg, P. (1993). Disordered methionine/homocysteine metabolism in premature vascular disease. Its occurrence, cofactor therapy and enzymology. Arteriosclerosis and Thrombosis 13, 1253–1260.Google Scholar
Edwards, R.L., Levine, J.B., Green, R., Duffy, M., Mathews, E., Brande, W. # Rickles, F.R. (1987). Activation of blood coagulation in Crohn's disease. Increased plasma fibrinopeptide A levels and enhanced generation of monocyte tissue factor activity. Gastroenterology 92, 329–337.Google Scholar
Engbersen, A.M.T., Franken, D.G., Boers, G.H.J., Stevens, E.M.B., Trijbels, F.J.M. # Blom, H.J. (1995). Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. American Journal of Human Genetics 56, 142–150.Google Scholar
Fenton, W.A. # Rosenberg, L.E. (1989). Inherited disorders of cobalamin transport and metabolism. In The Metabolic Basis of Inherited Disease. p. 2065 [Scriver, C. R., Beaudet, A. L., Sly, W. S. and Valle, D., editors]. New York: McGraw-Hill.Google Scholar
Finkelstein, J.D. (1990). Methionine metabolism in mammals. Journal of Nutritional Biochemistry 1, 228–237.Google Scholar
Frosst, P., Blom, H.J., Milos, R., Goyette, P., Sheppard, C.A., Matthews, R G., Boers, G.J.H., den Heijer, M., Kluijtmans, L.A.J., Van den Heuvel, L.P. # Rozen, R. (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics 10, 111–113.Google Scholar
Fryer, R.H., Wilson, B.D., Gubler, D.B., Fitzgerald, L.A. # Rodgers, G.M. (1993). Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arteriosclerosis and Thrombosis 13, 1327–1333.Google Scholar
Gallagher, P.M., Meleady, R., Shields, D.S., Tan, K.S., McMaster, D., Rozen, R., Evans, A., Graham, I.M. # Whitehead, A.S. (1996). Homocysteine and risk of premature coronary heart disease: evidence for a common gene mutation. Circulation 94, 2154–2158.Google Scholar
Gerritsen, T., Vaughn, J.G. # Waisman, H.A. (1962). The identification of homocystine in the urine. Biochemical and Biophysical Research Communications 9, 493496.Google Scholar
Glueck, C.J., Shaw, P., Lang, J.E., Tracy, T., Sieve-Smith, L. # Wang, Y. (1995). Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients. American Journal of Cardiology 75, 132–136.Google Scholar
Goyette, P., Frosst, P., Rosenblatt, D.S. # Rozen, R. (1995). Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. American Journal of Human Genetics 56, 1052–1059.Google Scholar
Goyette, P., Summer, J.S., Milos, R., Duncan, A.M.V., Rosenblatt, D.S., Matthews, R.G. # Rozen, R. (1994). Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nature Genetics 7, 195–200.Google Scholar
Graham, I.M., Daly, L.E., Refsum, H.M., Robinson, K., Brattström, L.E., Ueland, P.M., Palma-Reis, R.J. et al. (1997). Plasma homocysteine as a risk factor for vascular disease. JAMA: Journal of the American Medical Association 277, 1775–1781.Google Scholar
Green, R. # Jacobsen, D.W. (1995). Clinical implications of hyperhomocysteinaemia. In Folate in Health and Disease, pp. 75–122 [Lynn, Bailey, editor]. New York: Marcel Dekker.Google Scholar
Gregory, J.F. (1995). The bioavailability of folate. In Folate in Health and Disease, pp. 195–236 [Bailey, Lynn B., editor]. New York: Marcel Dekker.Google Scholar
Gunter, E.W., Bowman, B.A., Caudill, S.P., Twite, D.B., Adams, M.J. # Sampson, E.J. (1996). Results of an international round robin for serum and whole blood folate. Clinical Chemistry 42, 1689–94.Google Scholar
Guttormsen, A.B., Ueland, P.M., Nesthus, I., Nygard, O., Schneede, J., Vollset, S.E. # Refsum, H. (1996). Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (<40 μmol/liter)—the Hordaland homocysteine study. Journal of Clinical Investigation 98, 2174–2183.Google Scholar
Hajjar, K.A. (1993). Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. Journal of Clinical Investigation 91, 2873–2879.Google Scholar
Harker, L.A., Ross, R., Stichter, S.J. # Scott, C.R. (1976). Homocystine-induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis. Journal of Clinical Investigation 58, 731–741.Google Scholar
Harmon, D.L., Woodside, J.V., Yarnell, J.W.G., McMaster, D., Young, I.S., McCrum, E.E., Gey, K.F., Whitehead, A.S. # Evans, A.E. (1996). The common ‘thermo-labile’ variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM: Monthly Journal of the Association of Physicians 89, 571–577.Google Scholar
Jackson, L.J., O'Gorman, P.J., O'Connell, J., Cronin, C.C., Cotter, K.P. # Shanahan, F. (1997). Thrombosis in inflammatory bowel disease: clinical setting, procoagulant profile and factor V. QJM: Monthly Journal of the Association of Physicians 90, 183–188.Google Scholar
Jacob, R.A., Wu, M.M., Henning, S.M. # Swendseid, M.E. (1994). Homocysteine increases as folate decreases in plasma of healthy men during short term dietary folate and methyl group restriction. Journal of Nutrition 124, 1072–1080.Google Scholar
Jacques, P.F., Bostom, A.G., Williams, R.R., Ellison, R.C., Eckfeldt, J.H., Rosenberg, I.H., Selhub, J. # Rozen, R. (1996). Relation between folate status, a common mutation in methylenetetrahydrofolate reductase and plasma homocysteine concentrations. Circulation 93, 7–9.Google Scholar
Joosten, E., van den Berg, A., Riezler, R., Naurath, H.J., Lindenbaum, J., Stabler, S.P. # Allen, R.H. (1993). Metabolic evidence that deficiencies of vitamin B12 (cobalamin), folate and vitamin B6 occur commonly in elderly people. American Journal of Clinical Nutrition 58, 468–476.Google Scholar
Kahn, H.A. (1966). The Dorn study of smoking and mortality among US veterans: report on eight and one-half years of observation. National Cancer Institute Monograph 19, 1–125.Google Scholar
Kang, S.-S., Passen, E.L., Ruggie, N., Kong, P.W.K. # Sora, H. (1993). Thermolabile defect of methylenetetrahy-drofolate reductase in coronary artery disease. Circulation 88, 1463–1469.Google Scholar
Kang, S.-S., Wong, P.W.K. # Malinow, M.R. (1992). Hyperhomocyst(e)inemia as a risk factor for occlusive vascular disease. Annual Review of Nutrition 12, 279–298.Google Scholar
Kang, S.-S., Wong, P.W.K., Susmano, A., Sora, J., Norusis, M. # Ruggie, N. (1991). Thermolabile methylenetetrahy-drofolate reductase: an inherited risk factor for coronary artery disease. American Journal of Human Genetics 48, 536–545.Google Scholar
Kang, S.-S., Wong, P.W.K., Zhou, J. # Cook, H.Y. (1986). Preliminary report: total homocyst(e)ine in plasma and amniotic fluid of pregnant women. Metabolism 35, 889–891.Google Scholar
Kang, S.-S., Wong, P.W.K., Zhou, J., Sora, J., Lessick, M., Ruggie, N. # Grcevich, G. (1988 a). Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism 37, 611–613 (b).Google Scholar
Kang, S.-S., Zhou, J., Wong, P.W.K., Kowalisyn, J. # Strokosch, G. (1988 b). Intermediate homocysteinaemia: a thermolabile variant of methylenetetrahydrofolate reductase. American Journal of Human Genetics 43, 414–421 (a).Google Scholar
Kelly, P., McPartlin, J., Goggins, M., Weir, D.G. # Scott, J.M. (1997). Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. American Journal of Clinical Nutrition 65, 1790–1795.Google Scholar
Kirke, P.N., Molloy, A.M., Daly, L.E., Burke, H., Weir, D.G. # Scott, J.M. (1993). Maternal plasma folate and vitamin B12 are independent risk factors for neural tube defects. Quarterly Journal of Medicine 86, 703–708.Google Scholar
Kluijtmans, L.A.J., van den Heuvel, L.P.W.J., Boers, G.H.J., Frosst, P., Stevens, E.M.B., van Oost, B.A., den Heijer, M., Trijbels, F.J.M., Rosen, R. # Blom, H.J. (1996). Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. American Journal of Human Genetics 58, 35–41.Google Scholar
Konecky, N., Malinow, R., Tunick, P.A., Freedberg, R.S., Rosenzweig, B.P., Katz, E.S., Hees, D.L., Upson, B., Leung, B., Perez, J. # Kronzon, I. (1997). Correlation between plasma homocysteine and aortic atherosclerosis. American Heart Journal 133, 534–540.CrossRefGoogle Scholar
Kraus, J.P. (1994). Molecular basis of phenotype expression in homocysteinuria. Journal of Inherited Metabolic Disease 17, 383–390.Google Scholar
Kraus, J.P., Le, K., Swaroop, M., Ohura, T., Tahara, T., Rosenberg, L.E., Roper, M.D. # Kozich, V. (1993). Human cystathionine β-synthase cDNA: sequence, alternative splicing and expression in cultured cells. Human Molecular Genetics 2, 1633–1638.Google Scholar
Kutzbach, C. # Stokstad, E.L.R. (1971). Mammalian methylenetetrahydrofolate reductase. Partial purification, properties, and inhibition by S-adenosylmethionine. Biochimica et Biophysica Acta 250, 459–477.Google Scholar
Landgren, F., Israelsson, B., Lindgren, A., Hultberg, B., Andersson, A. # Brattström, L. (1995). Plasma homocysteine in acute myocardial infarction: homocysteine-lowering effect of folic acid. Journal of Internal Medicine 237, 381–388.Google Scholar
Law, M.R., Wald, N.J. # Thompson, S.G. (1994). By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? British Medical Journal 308, 367–372.Google Scholar
Lentz, S.R. # Sadler, J.E. (1993). Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. Blood 81, 683–689.Google Scholar
Levenson, J., Malinow, M.R., Giral, P.H., Razavian, M. # Simon, A. (1994). Increased homocysteine levels in human hypertension. Journal of Hypertension 12(Suppl. 3), S74.Google Scholar
Levine, S. (1993). Analytical inaccuracy for folic acid with a popular commercial vitamin B12/ folate kit. Clinical Chemistry 39, 2209–2210.Google Scholar
Loscalzo, J. (1996). The oxidant stress of hyperhomocyst(e)inemia. Journal of Clinical Investigation 98, 5–7.Google Scholar
Ma, J., Stampfer, M.J., Hennekens, C.H., Frosst, P., Selhub, J., Horsford, J., Malinow, M.R., Willett, W.C. # Rosen, R. (1996). Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine and risk of myocardial infarction in US physicians. Circulation 94, 2410–2416.Google Scholar
McCully, K.S. (1969). Vascular pathology of homocysteinuria: implications for the pathogenesis of arteriosclerosis. American Journal of Pathology 56, 111–128.Google Scholar
McCully, K.S. # Wilson, R.B. (1975). Homocysteine theory of arteriosclerosis. Atherosclerosis 22, 215–227.Google Scholar
McGown, E.L., Lewis, C.M., Dong, M.H. # Sauberlich, H.E. (1978). Results with commercial radioassay kits compared with microbiological assay of folate in serum and whole blood. Clinical Chemistry 24, 2186–2191.Google Scholar
McKeever, M.P., Weir, D.G., Molloy, A. # Scott, J.M. (1991). Betaine-homocysteine methyltransferase: organ distribution in man, pig and rat, and subcellular distribution in the rat. Clinical Science 81, 551–556.Google Scholar
Mahmud, N., Donnelly, S., Molloy, A., McPartlin, J., Casey, E.B., Scott, J. # Weir, D.G. (1998 a). Plasma homocysteine is raised in patients with rheumatoid arthritis independent of methylene tetrahydrofolate reductase genotype. British Journal of Rheumatology 37, A154.Google Scholar
Mahmud, N., Molloy, A., McPartlin, J., Scott, J.M. # Weir, D.G. (1998 b). Homozygosity for methylene reductase C677T variant is associated with low folate and hyperhomocysteinaemia in inflammatory bowel disease patients: important clinical complications. Gasrroenterology 114, G4221.Google Scholar
Malinow, M.R., Duell, P.B., Hess, D.L. et al. (1998). Reduction in plasma homocysteine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. New England Journal of Medicine 338, 1009–1015.Google Scholar
Malinow, M.R., Levenson, J., Giral, P., Nieto, F.J., Razavian, M., Segond, P. # Simon, A. (1995). Role of blood pressure, uric acid and hemorheological parameters on plasma homocyst(e)ine concentration. Atherosclerosis 114, 175–183.Google Scholar
Malinow, M.R., Nieto, F.J., Szklo, M., Chambless, L.E. # Bond, G. (1993). Carotid artery intimal medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. The Atherosclerosis Risk in Communities Study. Circulation 87, 1107–1113.Google Scholar
Malinow, M.R., Sexton, G., Averbuch, M., Grossman, M., Wilson, D. # Upson, B. (1990). Homocysteinaemia in daily practice: levels in coronary artery disease. Coronary Artery Disease 1, 215–220.Google Scholar
Matthews, R.G. (1984). Methionine metabolism in folate and pterins. In Chemistry and Biochemistry of Folates, vol. I, pp. 497–553 [Blakley, R.L. and Benkovic, S.J., editors]. New York: Wiley # Sons.Google Scholar
Matthews, R.G. # Haywood, B.J. (1979). Inhibition of pig liver methylenetetrahydrofolate reductase by dihydrofolate: some mechanistic and regulatory implications. Biochemistry 18, 4845–4851.Google Scholar
Mayer, E.L., Jacobsen, D.W. # Robinson, K. (1996). Homocysteine and coronary atherosclerosis. Journal of the American College of Cardiology 27, 517–527.Google Scholar
Molloy, A.M., Daly, S., Mills, J.L., Kirke, P.N., Whitehead, A.S., Ramsbottom, D., Conley, M.R., Weir, D.G. # Scott, J.M. (1997). Thermolabile variant of 5.10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349, 1591–1593.Google Scholar
Molloy, A.M., Mills, J.L., Kirke, P.N., Whitehead, A.S., Weir, D.G. # Scott, J.M. (1998). Whole blood folate values in subjects with different methylenetetrahydrofolate reductase genotypes: differences between the radio assay and microbiological assay. Clinical Chemistry (in press).Google Scholar
Molloy, A.M. # Scott, J.M. (1998). Microbiological assay for serum, plasma, and red cell folate using cryopreserved, microtiter plate method. Methods in Enzymology 281, 43–53.Google Scholar
Morrison, H.I., Schaubel, D., Desmeules, M. # Wigle, D.T. (1996). Serum folate and risk of fatal coronary heart disease. JAMA: Journal of the American Medical Association 275, 1893–1896.Google Scholar
Mudd, S.H., Finkelstein, J.D., Irreverre, F. # Laster, L. (1964). Homocystinuria: an enzymatic defect. Science 143, 1443–1445.Google Scholar
Mudd, S.H., Levy, H.L. # Skovby, F. (1995). Disorders of transsulfuration. In The Metabolic and Molecular Basis of Inherited Disease, pp. 1279–1327 [Scriver, C.R., Baendet, A.L., Sly, W. and Valle, D., editors]. New York: McGraw-Hill.Google Scholar
Naurath, J., Joosten, E., Riezler, R., Stabler, S.P., Allen, R.H. # Lindenbaum, J. (1995). Effects of vitamin B12, folate and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet 346, 85–89.Google Scholar
Neaton, J.D. # Wentworth, D. (1992). Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316,099 white men. Archives of Internal Medicine 152, 56–64.Google Scholar
Neugebauer, S., Baba, T., Kurokawa, K. # Watanabe, T. (1997). Defective homocysteine metabolism as a risk factor for diabetic retinopathy. Lancet 349, 473–474.Google Scholar
Nordstrom, M. # Kjellstrom, T. (1992). Age dependency of cystathionine β-synthase activity in human fibroblasts in homocyst(e)inaemia and atherosclerotic vascular disease. Atherosclerosis 94, 213–221.Google Scholar
Nygard, O., Nordehaug, J.E., Refsum, H., Ueland, F.M., Farstad, M. # Vollset, S.E. (1997). Plasma homocysteine levels and mortality in patients with coronary artery disease. New England Journal of Medicine 337, 230–236.Google Scholar
Oakley, G.P. (1997 a). Let's increase folic acid fortification and include vitamin B12. American Journal of Clinical Nutrition 65, 1889–1890.Google Scholar
Oakley, G.P. (1997 b). Folic acid deficiency's role expands beyond birth defects. Scientist 11, 10–11.Google Scholar
Ou, C.-Y., Stevenson, R.F., Brown, V.K., Schwartz, C.E., Allen, W.P., Khoury, M., Oakley, G.P. # Adams, M.J. (1995). C677T homozygosity associated with thermolabile 5,10 methylenetetrahydrofolate reductase as a risk factor for neural tube defects. American Journal of Human Genetics 57, A223.Google Scholar
Pancharuniti, N., Lewis, C.A., Sauberlich, H.E., Perkins, L.L., Go, R.C.P., Alvarez, J.O., Macaluso, M., Acton, R.T., Copeland, R.B., Cousins, A.L., Gore, T.B., Cornwell, P.E. # Roseman, J.M., (1994). Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease. American Journal of Clinical Nutrition 59, 940–948.Google Scholar
Papapetrou, C., Lynch, S.A., Burn, J. # Edwards, Y.H. (1996). Methylenetetrahydrofolate reductase and neural tube defects. Lancet 348, 58.Google Scholar
Parfrey, P.S. (1993). Cardiac and cerebrovascular disease in chronic uraemia. American Journal of Kidney Diseases 21, 77–80.Google Scholar
Perna, A.F., Ingrosso, D., Galletti, P., Zappia, V. # De Santo, N.G. (1996). Membrane protein damage and methylation reactions in chronic renal failure. Kidney International 50, 358–366.Google Scholar
Perry, I.J., Refsum, H., Morris, R.W., Ebrahim, S.B., Ueland, P.M. # Shaper, A.G. (1995). Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 346, 1395–1398.Google Scholar
Peterson, J.C. # Spena, J.D. (1998). Vitamins and progression of atherosclerosis in hyperhomocysteinaemia. Lancet 351, 263.Google Scholar
Petri, M., Roubenoff, R., Dallal, G.E., Nadeau, M.R., Selhub, J., # Rosenberg, I.H. (1996). Plasma homocysteine as a risk factor for atherothrombotic events in systemic lupus erythematosus. Lancet 348, 1120–1124.Google Scholar
Rasmussen, K., Moller, J., Lyngbak, M., Pedersen, A.M.H. # Dybkjaer, L. (1996). Age- and gender-specific reference intervals for total homocysteine and methylmalonic acid in plasma before and after vitamin supplementation. Clinical Chemistry 42, 630–636.Google Scholar
Refsum, H, Ueland, P.M., Nygard, 0. # Vollset, S.E. (1998). Homocysteine and cardiovascular disease. Annual Review of Medicine 49, 31–62.Google Scholar
Robillon, J.F., Canivet, B., Candito, M., Sadoul, J.L., Jullien, D., Morand, P., Chambon, P. # Freychet, P. (1994). Type I diabetes mellitus and homocyst(e)ine. Diabète et Métabolisme 20, 494–496.Google Scholar
Robinson, K., Gupta, A., Dennis, V., Arheart, K., Chaudhary, D., Green, R., Vigo, P., Mayer, E.L., Selhub, J., Kutner, M. # Jacobsen, D.W. (1997). Hyperhomocysteinaemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations. Circulation 94, 2743–2748.Google Scholar
Robinson, K., Mayer, E., Miller, D., Green, R., van Lente, F., Gupta, A., Kottke-Marchant, K., Savon, S.R., Selhub, J., Nissen, S.E. et al. (1995). Hyperhomocysteinemia and low pyridoxal phosphate: common and independent reversible risk factors for coronary artery disease. Circulation 92, 2825–2830.Google Scholar
Rodgers, G.M. # Conn, M.T. (1990). Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 75, 895–901.Google Scholar
Rosenblatt, D.S. (1995). Inherited disorders of folate transport. In The Metabolic and Molecular Basis of Inherited Disease, pp. 821–844 [Scriver, C. R., editor]. New York: McGraw-Hill.Google Scholar
Roubenoff, R., Delloripa, P., Nadeaa, M.R., Abad, L.W., Muldoon, B.A., Selhub, J. # Rosenberg, I.H. (1997). Abnormal homocysteine metabolism in rheumatoid arthritis. Arthritis and Rheumatism 40, 718–722.Google Scholar
Scott, J.M. # Weir, D.G. (1981). The methyl folate trap. Lancet ii, 337–340.Google Scholar
Scott, J.M. # Weir, D.G. (1996). Homocysteine and cardiovascular disease. QJM: Monthly Journal of the Association of Physicians 89, 561–563.Google Scholar
Scott, J.M., Dinn, J.J., Wilson, P. # Weir, D.G. (1981). Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet ii, 334–337.Google Scholar
Selhub, J., Jacques, P.F., Bostom, A.G., D'Agostino, R.B., Wilson, P.W.F., Belanger, A.J., O'Leary, D.H., Wolf, P.A., Schaefer, E.J. # Rosenberg, I.H. (1995). Association between plasma homocysteine concentrations and extracranial carotid artery stenosis. New England Journal of Medicine 332, 286–291.Google Scholar
Selhub, J., Jacques, P.F., Wilson, P.W.F., Rush, D. # Rosenberg, I.H. (1993). Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA: Journal of the American Medical Association 270, 2693–2698.Google Scholar
Skovby, F. (1985). Homocystinuria, clinical, biochemical and genetic aspects of cystathionine beta-synthase and its deficiency in man. Acta Paediatrica Scandinavica Suppl. 321, 1–21.Google Scholar
Skovby, F., Kraus, J.P. # Rosenberg, L.E. (1984). Biosynthesis of human cystathionine β-synthase in cultured fibroblasts. Journal of Biological Chemistry 259, 583–587.Google Scholar
Stabler, S.P., Allen, R.H., Savage, D.G. # Lindenbaum, J. (1990). Clinical spectrum and diagnosis of cobalamin deficiency. Blood 76, 871–881.Google Scholar
Stamler, J.S., Osborne, J.A., Jaraki, O., Rabbani, L.E., Mullins, M., Singel, D. # Loscalzo, J. (1993). Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. Journal of Clinical Investigation 91, 308–318.Google Scholar
Stampfer, M.J., Malinow, M.R., Willett, W.C., Newcomer, L.M., Upson, B., Ullmann, D., Tishler, P.V. # Hennekens, C.H. (1992). A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA: Journal of the American Medical Association 268, 877–881.Google Scholar
Talbot, R.W., Heppell, J., Dozois, R.R. # Beart, R.W. (1986). Vascular complications of inflammatory bowel disease. Mayo Clinic Proceedings 61, 140–145.Google Scholar
Tamura, T., Johnston, K.E. # Bergman, S.M. (1996). Homocysteine and folate concentrations in blood from patients treated with hemodialysis. Journal of rhe American Society of Nephrology 7, 2414–2418.Google Scholar
Tsai, J.-C., Perrella, M.A., Yoshizumi, M., Hsieh, C.M., Haber, E., Schlegel, R. # Lee, M.E. (1994). Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proceedings of Nationa1 Academy of Sciences of the USA 91, 6369–6373.Google Scholar
Tsai, M.Y., Bignell, M., Schwichtenberg, K. # Hanson, N.Q. (1996 a). High prevalence of a mutation in the cystathionine β-synthase gene. American Journal of Human Genetics 59, 1262–1267.Google Scholar
Tsai, M.Y., Garg, U., Key, N.S., Hanson, N.Q., Suh, A. # Schwichtenberg, K. (1996 b). Molecular and biochemical approaches in the identification of heterozygotes for homocysteinuria. Atherosclerosis 122, 69–77.Google Scholar
Tucker, K.L., Mahnken, B., Wilson, P.W.F., Jacques, P. # Selhub, J. (1996). Folic acid fortification of the food supply. Potential benefits and risks for the elderly population. JAMA: Journal of the American Medical Association 276, 1879–1885.Google Scholar
Ueland, P.M. # Refsum, H. (1989). Plasma homocysteine - a risk factor for vascular disease: plasma levels in health, disease and drug therapy. Journal of Laboratory and Clinical Medicine 114, 473–501.Google Scholar
Ueland, P.M., Refsum, H., Stabler, S.P., Malinow, M.R., Andersson, A. # Allen, R.H. (1993). Total homocysteine in plasma or serum: methods and clinical application. Clinical Chemistry 39, 1764–1779.Google Scholar
van Bockxmeer, F.M., Mamotte, C.D.S., Vasikaran, S.D. # Taylor, R.R. (1997). Methylenetetrahydrofolate reductase gene and coronary artery disease. Circulation 95, 21–23.Google Scholar
van der Mooren, M.J., Wouters, M.G.A.J., Blom, H.J., Schellekens, L.A., Eskes, T.K.A.B. # Rolland, R. (1994). Hormone replacement therapy may reduce high serum homocysteine in post-menopausal women. European Journal of Clinical Investigation 24, 733–736.Google Scholar
van der Put, N.M.J., Eskes, T.K.A.B. # Blom, H.J. (1997). Is the common C677C-T mutation in the methylenete trahydrofolate reductase gene a risk factor for neural tube defects? A meta analysis. QJM: Monthly Journal of the Association of Physicians 90, 111–115.Google Scholar
van der Put, N.M.J., Steegers-Theunissen, R.P.M., Frosst, P., Trijbels, F.J.M., Eskes, T.K.A.B., van den Heuvel, L.P., Mariman, E.C.M., den Heyer, M., Rozen, R. # Blom, H.J. (1995). Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 346, 1070–1071.Google Scholar
Vasikaran, B.D. # van Bockxmeer, F.M. (1997). Mild to moderate hyperhomocysteinaemia; a risk factor for vascular disease. Clinical Biochemistry Reviews 18, 55–62.Google Scholar
Verhoef, P., Hennekens, C.H., Allen, R.H., Stabler, S.P., Willett, W.C. # Stampfer, M.J. (1997). Plasma total homocysteine and risk of angina pectoris with subsequent coronary artery bypass surgery. American Journal of Cardiology 79, 799–801.Google Scholar
Verhoef, P., Hennekens, C.H., Malinow, M.R., Koh, F.J., Willett, W.C. # Stampfer, M.J. (1994). A prospective study of plasma homocyst(e)ine and risk of ischemic stroke. Stroke 25, 1924–1930.CrossRefGoogle Scholar
Verhoef, P. # Stampfer, M.J. (1995). Prospective studies of homocysteine and cardiovascular disease. Nutrition Reviews 33, 283–288.Google Scholar
Wald, N.J., Watt, H.C., Law, M.R., Weir, D.G., McPartlin, J. # Scott, J.M. (1998). Homocysteine and ischaemic heart disease: results of a prospective study with implications on prevention. Archives of Internal Medicine 158, 862–867.Google Scholar
Wang, J., Dudman, N.P.B., Wilcken, D.E.L.M. # Lynch, J.F. (1992). Homocysteine catabolism: levels of 3 enzymes in cultured human vascular endothelium and their relevance to vascular disease. Atherosclerosis 97, 97–106.Google Scholar
Ward, M., McNulty, H., McPartlin, J., Strain, J.J., Weir, D.G. # Scott, J.M. (1997). Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. QJM; Monthly Journal of the Association of Physicians 90, 519–524.Google Scholar
Weir, D.G. # Scott, J.M. (1995). The biochemical basis of the neuropathy in cobalamin deficiency. In Clinical Haematology: Megaloblastic Anaemia, vol. 8, pp. 479–497 [Wickramasinghe, S.N., editor]. London: Bailliere.Google Scholar
Whitehead, A.S., Gallagher, P., Mills, J.L., Kirke, P.N., Burke, H., Molloy, A.M., Weir, D.G., Shields, D.C. # Scott, J.M. (1995). A genetic defect in 5,10-methylenetetrahydrofolate reductase in neural tube defects. QJM: Monthly Journal of the Association of Physicians 88, 763–766.Google Scholar
Wilcken, D.E.L. (1997). MTHFR 677C → T mutation, folate intake, neural-tube defect, and risk of cardiovascular disease. Lancet 350, 603–604.Google Scholar
Wilcken, D.E.L., Gupta, V.J. # Reddy, S.G. (1980). Accumulation of sulfur-containing amino acids including cysteine-homocysteine in patients on maintenance hemodialysis. Clinical Science 58, 427–430.Google Scholar
Wilcken, D.E.L., Wang, X.L., Sim, A.S. # McCredie, R.M. (1996). Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Arteriosclerosis, Thrombosis and Vascular Biology 16, 878–882.Google Scholar
Wilcken, D.E.L. # Wilcken, B. (1976). The pathogenesis of coronary artery disease: a possible role for methionine metabolism. Journal of Clinical Investigation 57, 1079–1082.Google Scholar
Wild, J., Schorah, C.J., Maude, K. # Levene, M.I. (1996a). Folate intake in young women and their knowledge of preconceptional folate supplementation to prevent neural tube defects. European Journal of Obstetrics and Gynecology and Reproductive Biology 70, 185–189.Google Scholar
Wild, J., Schorah, C.J., Maude, K. # Levene, M.I. (1996b). Girls should be taught at school about importance of folic acid. British Medical Journal 312, 974.Google Scholar
Wouters, M.G.A.J., Moorrees, M.T.E.C., van der Mooren, M.J., Bloom, H.J., Boers, G.H.J., Schellekens, L.A., Thomas, C.M.G. # Eskes, T.K.A.B. (1995). Plasma homocysteine and menopausal status. European Journal of Clinical Investigation 25, 801–805.Google Scholar