Hostname: page-component-cd9895bd7-gvvz8 Total loading time: 0 Render date: 2024-12-26T09:08:56.608Z Has data issue: false hasContentIssue false
  • English
  • Français

B-vitamins, homocysteine metabolism and CVD

Published online by Cambridge University Press:  07 March 2007

J. J. Strain ,
L. Dowey ,
M. Ward ,
K. Pentieva  and
H. McNulty
J. J. Strain*
Affiliation:
Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Coleraine, BT52 1SA, UK
L. Dowey
Affiliation:
Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Coleraine, BT52 1SA, UK
M. Ward
Affiliation:
Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Coleraine, BT52 1SA, UK
K. Pentieva
Affiliation:
Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Coleraine, BT52 1SA, UK
H. McNulty
Affiliation:
Northern Ireland Centre for Food and Health (NICHE), University of Ulster, Coleraine, BT52 1SA, UK
*
*Corresponding author: Professor J. J. Strain, fax +44 28 70324965, email JJ.Strain@ulster.ac.uk
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The present review focuses on the B-vitamins, i.e. folate, vitamin B12, vitamin B6 and riboflavin, that are involved in homocysteine metabolism. Homocysteine is a S-containing amino acid and its plasma concentrations can be raised by various constitutive, genetic and lifestyle factors, by inadequate nutrient status and as a result of systemic disease and various drugs. Hyperhomocysteinaemia is a modest independent predictor of CVD and stroke, but causality and the precise pathophysiological mechanism(s) of homocysteine action remain unproven. The predominant nutritional cause of raised plasma homocysteine in most healthy populations is folate insufficiency. Vitamin B12 and, to a lesser extent, vitamin B6 are also effective at lowering plasma homocysteine, especially after homocysteine lowering by folic acid in those individuals presenting with raised plasma homocysteine. However, riboflavin supplementation appears to be effective at lowering plasma homocysteine only in those individuals homozygous for the T allele of the C677 T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene. This gene codes for the MTHFR enzyme that produces methyltetrahydrofolate, which, in turn, is a substrate for the remethylation of homocysteine by the vitamin B12-dependent enzyme methionine synthase. Individuals with the MTHFR 677 TT genotype are genetically predisposed to elevated plasma homocysteine, and in most populations have a markedly higher risk of CVD.

Keywords

HomocysteineFolateVitamin B12Vitamin B6Riboflavin
Type
Symposium on ‘Micronutrient interactions and public health’
Information
Proceedings of the Nutrition Society , Volume 63 , Issue 4 , November 2004 , pp. 597 - 603
Copyright
Copyright © The Nutrition Society 2004

References

Brattstrom, L, Wilcken, DE, Ohrvik, J & Brudin, L (1998) Common methylenetrahydrofolate reductase gene mutation leads to hyperhomocysteineamia but not to vascular disease: the result of a meta-analysis. Circulation 98, 2520–2526CrossRefGoogle Scholar
Carson, NAJ & Neill, DW (1962) Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland. Archives of Diseases in Childhood 37, 505–513CrossRefGoogle Scholar
Castro, R, Rivera, I, Struys, EA, Jansen, EEW, Ravasco, P, Camilo, ME, Blom, HJ, Jakobs, C, de Almeida, IT (2003) Increased homocysteine and S -adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clinical Chemistry 49, 1292–1296CrossRefGoogle ScholarPubMed
Chambers, JC, Ueland, PM, Obeid, OA, Wrigley, J, Refsum, H & Kooner, JS (2000) Improved vascular endothelial function after oral B vitamins: An effect mediated through reduced concentrations of free plasma homocysteine. Circulation 102, 2479–2483CrossRefGoogle Scholar
Davey-Smith, G & Ebrahim, S (2003) ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease. International Journal of Epidemiology 32, 1–22CrossRefGoogle Scholar
Dawson, H, Collins, G, Pyle, R, Deep-Duxit, V & Taub, DD (2004) The immunoregulatory effects of homocysteine and its intermediates on T-lymphocyte function. Mechanisms of Ageing and Development 125, 107–110CrossRefGoogle ScholarPubMed
de, Bree, A, Verschuren, WMM, Kromhout, D, Kluijtmans, LAJ Blom, HJ (2002) Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease. Pharmacological Reviews 54, 599–618Google Scholar
den, Heijer, M, Brouwer, IA, Bos, GM, Blom, HJ, van der, Put, NM, Spaans, AP, Rosendaal, FR, Thomas, CM, Haak, HL, Wijermans, PW & Gerrits, WB (1998) Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers. Arteriosclerosis, Thrombosis and Vascular Biology 18, 356–361Google Scholar
Dong, C, Yoon, W, Goldschmidt-Clemont, PJ (2002) DNA methylation and atherosclerosis. Journal of Nutrition 132 2406S – 2409SCrossRefGoogle ScholarPubMed
Frisco, S, Choi, SW, Girelli, D, Mason, JB, Doinikouski, GG, Bagley, PJ, Olivieri, O, Jacques, PF, Rosenberg, IH, Corrocher, R & Selhub, J (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proceedings of the National Academy of Sciences USA 99, 5606–5611CrossRefGoogle Scholar
Frosst, P, Blom, HJ, Milos, R, Goyette, P, Shepard, CA, Matthews, RG, Boers, GJ, den, Heijer, M, Kluijtmans, LA van, den & Heuvel, LP (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics 10, 111–113CrossRefGoogle ScholarPubMed
Gerritsen, T, Vaughn, JG & Waisman, HA (1962) The identification of homocysteine in the urine. Bichemical and Biophysical Research Communications 9, 493–496CrossRefGoogle ScholarPubMed
Herrmann, W, Schorr, H, Obeid, R & Geisel, J (2003) Vitamin B 12 status, particularly holotranscobalamin 11 and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. American Journal of Clinical Nutrition 78, 131–136CrossRefGoogle ScholarPubMed
Homocysteine Lowering, Trialists' Collaboration (1998) Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. British Medical Journal 316, 894–898CrossRefGoogle Scholar
Homocysteine, Studies Collaboration (2002) Homocysteine and risk of ischaemic heart disease and stroke. Journal of the American Medical Association 288, 2015–2022CrossRefGoogle Scholar
Hung, C-J, Huang, P-C, Lu, S-C, Li, Y-H, Huang, H-B, Lin, B-F, Chang, S-J, Chou, H-F (2002) Plasma homocysteine levels in Taiwanese vegetarians are higher than those of omnivores. Journal of Nutrition 132, 152–158CrossRefGoogle ScholarPubMed
Hustad, S, Ueland, PM, Vollset, SE, Zhang, Y, Bjorke-Monsen, A & Schneede, J (2000) Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clinical Chemistry 46, 1065–1071CrossRefGoogle ScholarPubMed
Jacques, PF, Kalmbach, R, Bagley, PJ, Russo, GT, Rogers, G, Wilson, PWF, Rosenberg, IH & Selhub, J (2002) The relationship between riboflavin and plasma total homocysteine in the Framingham Offspring Cohort is influenced by folate status and the C677T transition in the methylenetetrahydrofolate reductase gene. Journal of Nutrition 132, 283–288CrossRefGoogle ScholarPubMed
Jacques, PF, Selhub, J, Bostom, AG, Wilson, PW & Rosenberg, IH (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. New England Journal of Medicine 340, 1449–1454CrossRefGoogle ScholarPubMed
Kelly, PJ, Kistler, JP, Shih, VE, Mandell, R, Atassi, N, Barron, M, Lee, H, Silveira, S & Furie, KL (2004) Inflammation, homocysteine, and vitamin B 6 status after ischemic stroke. Stroke 35, 12–15CrossRefGoogle ScholarPubMed
Kelly, PJ, Shih, VE, Kistler, JP, Barron, M, Lee, H, Mandell, R & Furie, KL (2003) Low vitamin B 6 but not homocysteine is associated with increased risk of stroke and transient ischemic attack in the era of folic acid grain fortification. Stroke 34, e51–e54CrossRefGoogle Scholar
Klerk, M, Verhoef, P, Clarke, R, Blom, HJ, Kok, FJ, Schouten, EG the MTHFR, Studies Collaboration Group (2002) MTHFR 677C→T polymorphism and risk of coronary heart disease – A meta analysis. Journal of the American Medical Association 288, 2023–2031CrossRefGoogle Scholar
Liaugaudas, G, Jacques, PF, Selhub, J, Rosenberg, IH & Bostum, AG (2001) Renal sufficiency, vitamin B 12 status, and population attributable risk for mild hyperhomocysteinemia among coronary artery disease patients in the era of folic acid-fortified cereal grain flour. Arteriosclerosis, Thrombosis and Vascular Biology 21, 849–851CrossRefGoogle Scholar
McCully, KS (1969) Vascular pathology of homocysteinamia: implications for the pathogenesis of arteriosclerosis. American Journal of Pathology 56, 111–128Google ScholarPubMed
McKinley, M, McNulty, H, McPartlin, J, Strain, JJ, Pentieva, K, Ward, M, Weir, DG & Scott, JM (2001) Low-dose vitamin B 6 effectively lowers fasting plasma homocysteine in healthy elderly persons who are folate and riboflavin replete. American Journal of Clinical Nutrition 73, 759–764CrossRefGoogle ScholarPubMed
McKinley, MC, McNulty, H, McPartlin, J, Strain, JJ & Scott, JM (2002) Effect of riboflavin supplementation on plasma homocysteine in elderly people with low riboflavin status. European Journal of Clinical Nutrition 56, 850–856CrossRefGoogle ScholarPubMed
McNulty, H, Dowey, LC, Scott, JM, Molloy, AM, McAnena, LB, Hughes, JP, Ward, W & Strain, JJ (2003) Riboflavin supplementation lowers plasma homocysteine in individuals homozygous for the MTHFR C677T polymorphism. Journal of Inherited Metabolic Disease 26, Suppl. 1, 12 AbstrGoogle Scholar
McNulty, H, McKinley, MC, Wilson, B, McPartlin, J, Strain, JJ, Weir, DG & Scott, JM (2002) Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. American Journal of Clinical Nutrition 76, 436–441CrossRefGoogle ScholarPubMed
Mangoni, AA & Jackson, SHD (2002) Homocysteine and cardiovascular disease: current evidence and future prospects. American Journal of Medicine 112, 556–565CrossRefGoogle ScholarPubMed
Mann, NJ, Li, D, Sinclair, AJ, Dudman, NPB, Guo, XW, Elsworth, GR, Wilson, AK & Felly, FD (1999) The effect of diet on plasma homocysteine concentrations in healthy male subjects. European Journal of Clinical Nutrition 53, 895–899CrossRefGoogle ScholarPubMed
Nygard, O, Refsum, H, Ueland, PM & Vollset, SE (1998) Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. American Journal of Clinical Nutrition 67, 263–270CrossRefGoogle ScholarPubMed
Olthof, MR, van Vliet, T, Boelsma, E, Verhoef, P (2003) Low-dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. Journal of Nutrition 133, 4135–4138CrossRefGoogle ScholarPubMed
Quinlivan, EP, McPartlin, J, McNulty, H, Ward, M, Strain, JJ, Weir, DG & Scott, JM (2002) Importance of both folic acid and vitamin B 12 in reduction of risk of vascular disease. Lancet 359, 227–228CrossRefGoogle ScholarPubMed
Rimm, EB, Willett, WC, Hu, FB, Sampson, L, Colditz, GA, Manson, JE, Hennekens, C & Stampfer, MJ (1998) Folate and vitamin B 6 from diet and supplements in relation to risk of coronary heart disease among women. Journal of the American Medical Association 279, 359–364CrossRefGoogle ScholarPubMed
Robinson, K (2000) Homocysteine, B vitamins, and risk of cardiovascular disease. Heart 83, 127–130CrossRefGoogle ScholarPubMed
Schnyder, G, Flammer, Y, Roffi, M, Pin, R & Hess, OM (2002) Plasma homocysteine levels and late outcome after coronary angioplasty. Journal of the American College of Cardiology 40, 1769–1776CrossRefGoogle ScholarPubMed
Schnyder, G, Roffi, M, Pin, R, Flammer, Y, Lange, H, Eberli, FR, Meier, B, Turi, ZG & Hess, OM (2001) Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. New England Journal of Medicine 345, 1593–1600CrossRefGoogle ScholarPubMed
Schwahn, BC, Chen, ZT, Laryea, MD, Wendel, U, Lussier-Cacan, S, Genest, J, Mar, MH, Zeisel, SH, Castro, C, Garrow, T & Rozen, R (2003) Homocysteine-betaine interactions in a murine model of 5,10-methylenetetrahydrofolate reductase deficiency. FASEB Journal 17, U163–U187CrossRefGoogle Scholar
Scott, JM (1997) Bioavailability of vitamin B 12. European Journal of Clinical Nutrition 51, S49–S53 Suppl. 1Google Scholar
Stern, LL, Shane, B, Bagley, PJ, Nadeau, M, Shih, V & Selhub, J (2003) Combined marginal folate and riboflavin status affect homocysteine methylation in cultured immortalized lymphocytes from persons homozygous for the MTHFR C677T mutation. Journal of Nutrition 133, 2716–2720Google Scholar
Tighe, P, Ward, M, McNulty, H, Finnegan, O, Strain, JJ, Dunne, A, Molloy, AM & Scott, JM (2004) Plasma homocysteine response to folic acid intervention in ischaemic heart disease patients: implications for food fortification policy Proceedings of the Nutrition Society 63Google Scholar
Toole, JF, Malinow, MR, Chambless, LE Spence, JD, Pettigrew, LC, Howard, VJ, Slides, EG, Wong, C-H, Stampfer M (2004) Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction and death. Journal of the American Medical Association 291, 565–575CrossRefGoogle ScholarPubMed
Ubbink, JB (1994) Vitamin nutrition status and homocysteine: an atherogenic risk factor. Nutrition Reviews 52, 383–387CrossRefGoogle ScholarPubMed
Van Oort, FVA, Melse-Boostra, A, Brouwer, IA, Clarke, R, West, CE, Katan, MB, Verhoef, P (2003) Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study. American Journal of Clinical Nutrition 77, 1318–1323CrossRefGoogle ScholarPubMed
Wald, DS, Bishop, L, Wald, NJ, Law, M, Hennessy, E, Weir, D, McPartlin, J & Scott, J (2001) Randomized trial of folic acid supplementation and serum homocysteine levels. Archives of Internal Medicine 161, 695–700CrossRefGoogle ScholarPubMed
Wald, DS, Law, M & Morris, JK (2002) Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. British Medical Journal 325, 1202–1206CrossRefGoogle ScholarPubMed
Ward, M, McNulty, H, McPartlin, J, Strain, JJ, Weir, DG & Scott, JM (1997) Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. Quarterly Journal of Medicine 90, 519–524CrossRefGoogle ScholarPubMed
Yamada, K, Chen, Z, Rozen, R & Matthews, RG (2001) Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Nature Structural Biology 6, 359–365Google Scholar