Journal of Applied Genetics

, Volume 49, Issue 3, pp 267–282 | Cite as

Homocysteine,MTHFR gene polymorphisms, and cardio-cerebrovascular risk

Review Article

Abstract

Vascular diseases are commonly associated with traditional risk factors, but in the last decade scientific evidence has suggested that elevated plasma levels of homocysteine are associated with an increased risk of atherosclerosis and cardiovascular ischaemic events. Cardio- and cerebrovascular diseases are multifactorial, as their aetiopathogenesis is determined by genetic and environmental factors and by gene-gene and gene-environment interactions. Experimental studies have shown that many possible mechanisms are implicated in the pro-atherogenic effect of homocysteine. Hyperhomocysteinaemia may confer a mild risk alone, but it increases the risk of disease in association with other factors promoting vascular lesions. Variants in genes encoding enzymes involved in homocysteine metabolism, or depletion of important cofactors or substrates for those enzymes, including folate, vitamin B12 and vitamin B6, may result in elevated plasma homocysteine levels. Several studies have been performed to elucidate the genetic determinant of hyperhomocysteinaemia in patients with vascular disease, and theMTHFR 677C>T polymorphism is the one most extensively investigated. However, the lack of homogeneity in the data and the high number of factors influencing plasma homocysteine concentrations remain conflicting. Moreover, studies on the evaluation of therapeutic interventions in improving the atherogenic profile, lowering plasma homocysteine levels, and preventing vascular events, have shown inconsistent results, which are reviewed in this paper. More prospective, double-blind, randomized studies, including folate and vitamin B interventions, and genotyping for polymorphisms in genes involved in homocysteine metabolism, might better define the relationship between mild hyperhomocysteinaemia and vascular damage.

Keywords

cardiovascular disease cerebrovascular disease gene hyperhomocysteinaemia MTHFR polymorphisms vascular risk factors 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abbate R, Sofi F, Brogi D, Marcucci R, 2003. Emerging risk factors for ischemic stroke. Neurol Sci May; 24 Suppl 1: S11–12.PubMedCrossRefGoogle Scholar
  2. Alfthan G, Pekkanen J, Jauhiainen M, Pitkäniemi J, Karvonen M, Tuomilehto J, et al. 1994. Relation of serum homocysteine and lipoprotein (a) concentrations to atherosclerotic disease in a prospective Finnish population based study. Atherosclerosis 106: 9–19.PubMedCrossRefGoogle Scholar
  3. Alluri RV, Mohan V, Komandur S, Chawda K, Chaudhuri JR, Hasan Q, 2005.MTHFR C677T gene mutation as a risk factor for arterial stroke: a hospital based study. Eur J Neurol 12: 40–44.PubMedCrossRefGoogle Scholar
  4. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug JE, 1995. Serum total homocysteine and coronary artery disease. Int J Epidemiol 24: 704–709.PubMedCrossRefGoogle Scholar
  5. Austin RC, Lentz SR, Werstuck GH, 2004. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. Jul: 11 Suppl 1: S56–64.PubMedCrossRefGoogle Scholar
  6. Bailey LB, Gregory JF 3rd, 1999. Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr 129: 919–922.PubMedGoogle Scholar
  7. Bendini MG, Lanza GA, Mazza A, Giordano A, Leggio M, Menichini G, et al. 2007. Risk factors for cardiovascular diseases: what is the role for homocysteine? G Ital Cardiol 8: 148–160.Google Scholar
  8. Berg K, Malinow MR, Kierulf P, Upson B, 1992. Population variation and genetics of plasma homocyst(e)ine level. Clin Genet 41: 315–321.PubMedCrossRefGoogle Scholar
  9. Bezemer ID, Doggen CJ, Vos HL, Rosendaal FR, 2007. No association between the commonMTHFR 677C>T polymorphism and venous thrombosis: results from the MEGA study. Arch Intern Med 167: 497–501.PubMedCrossRefGoogle Scholar
  10. Bilsborough W, Green DJ, Mamotte CD, van Bockxmeer FM, O’Driscoll GJ, Taylor RR, 2003. Endothelial nitric oxide synthase gene polymorphism, homocysteine, cholesterol and vascular endothelial function. Atherosclerosis 169: 131–138.PubMedCrossRefGoogle Scholar
  11. Blasco C, Caballería J, Deulofeu R, Lligońa A, Parés A, Lluis JM, et al. 2005. Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics. Alcohol Clin Exp Res 29: 1044–1048.PubMedCrossRefGoogle Scholar
  12. Boers GH, Smals AG, Trijbels FJ, Fowler B, Bakkeren JA, Schoonderwaldt HC, et al. 1985. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 313: 709–715.PubMedCrossRefGoogle Scholar
  13. Bosco P, Guéant-Rodriguez RM, Anello G, Spada R, Romano A, Fajardo A, et al. 2006. Association of homocysteine (but not ofMTHFR 677C>T,MTR 2756A>G,MTRR 66A>G andTCN2 776C>G) with ischaemic cerebrovascular disease in Sicily. Thromb Haemost 96: 154–159.PubMedGoogle Scholar
  14. Bostom AG, Lathrop L, 1997. Hyperhomocysteinemia in end-stage renal disease: prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int 52: 10–20.PubMedCrossRefGoogle Scholar
  15. Bostom AG, Shemin D, Verhoef P, Nadeau MR, Jacques PF, Selhub J, et al. 1997. Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients: a prospective study. Arterioscler Thromb Vasc Biol 17: 2554–2558.PubMedGoogle Scholar
  16. Bostom AG, Silbershatz H, Rosenberg IH, Selhub J, D’Agostino RB, Wolf PA, et al. 1999. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med 159: 1077–1080.PubMedCrossRefGoogle Scholar
  17. Botto LD, Yang Q, 2000. 5,10-Methylenetetra-hydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 151: 862–877.PubMedGoogle Scholar
  18. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG, 1995. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274: 1049–1057.PubMedCrossRefGoogle Scholar
  19. Brattström LE, Hardebo JE, Hultberg BL, 1984. Moderate homocysteinemia: a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke 15: 1012–1015.PubMedGoogle Scholar
  20. Brattström L, Wilcken DE, Ohrvik J, Brudin L, 1998. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation. 98: 2520–2526.PubMedGoogle Scholar
  21. Brown K, Luddington R, Baglin T, 1998. Effect of the MTHFRC677T variant on risk of venous thromboembolism: interaction with factor V Leiden and prothrombin (F2G20210A) mutations. Br J Haematol 103: 42–44.PubMedCrossRefGoogle Scholar
  22. Caramia G, Belardinelli R, 2006. Iperomocisteinemia in etŕ evolutiva e aspetti nutrizionali dei folati: un fattore di rischio cardiovascolare precoce. Monadi Arch Chest Dis 66: 275–285.Google Scholar
  23. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani AD, 2005. Homocysteine and stroke: evidence on a causal link from Mendelian randomisation. Lancet 365: 224–232.PubMedGoogle Scholar
  24. Cattaneo M, Vecchi M, Zighetti ML, Saibeni S, Martinelli I, Omodei P, et al. 1998. High prevalence of hyperhomocysteinemia in patients with inflammatory bowel disease: a pathogenic link with thromboembolic complications? Thromb Haemost 80: 542–545.PubMedGoogle Scholar
  25. Cattaneo M, Chantarangkul V, Taioli E, Santos JH, Tagliabue L, 1999. The G20210A mutation of the prothrombin gene in patients with previous first episodes of deep-vein thrombosis: prevalence and association with factor V G1691A, methylenetetrahydrofolate reductase C677T and plasma prothrombin levels. Thromb Res 93: 1–8.PubMedCrossRefGoogle Scholar
  26. Chambers JC, McGregor A, Jean-Marie J, Obeid OA, Kooner JS, 1999. Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy. Circulation 99: 1156–1160.PubMedGoogle Scholar
  27. Chwatko G, Boers GHJ, Strauss KA, Shih DM, Jakubowski H, 2007. Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice. FASEB J 21: 1707–1713.PubMedCrossRefGoogle Scholar
  28. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM, 1998. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55: 1449–1455.PubMedCrossRefGoogle Scholar
  29. Coppola A, Albisinni R, Madonna P, Pagano A, Cerbone AM, Di Minno G, 1997. Platelet and monocyte variables in homocystinuria due to cystathionine-beta-synthase deficiency. Haematologica 92: 189–190.Google Scholar
  30. Cravo ML, Glória LM, Selhub J, Nadeau MR, Camilo ME, Resende MP, et al. 1996. Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B-12, and vitamin B-6 status. Am J Clin Nutr 63: 220–224.PubMedGoogle Scholar
  31. Cronin S, Furie KL, Kelly PJ, 2005. Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative metaanalysis. Stroke 36: 1581–1587.PubMedCrossRefGoogle Scholar
  32. Dedoussis GV, Panagiotakos DB, Pitsavos C, Chrysohoou C, Skoumas J, Choumerianou D, et al. 2005. An association between the methyl-enetetrahydrofolate reductase (MTHFR) C677T mutation and inflammation markers related to cardiovascular disease. Internat J Cardiol 100: 409–414.CrossRefGoogle Scholar
  33. De Luca G, Suryapranata H, Gregorio G, Lange H, Chiariello M, 2005. Homocysteine and its effects on in-stent restenosis. Circulation 112: e307–311.CrossRefGoogle Scholar
  34. den Heijer M, Koster T, Blom HJ, Bos GM, Briet E, Reitsma PH, et al. 1996. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 334: 759–762.CrossRefGoogle Scholar
  35. De Vecchi AF, Bamonti Catena F, 1999. L’omocisteina in dialisi peritoneale. Giornale Italiano di Nefrologia 6: 654–663.Google Scholar
  36. Dikmen M, Ozbabalik D, Gunes HV, Degirmenci I, Bal C, Ozdemir G, et al. 2006. Acute stroke in relation to homocysteine and methylenetetra-hydrofolate reductase gene polymorphisms. Acta Neurol Scand 113: 307–314.PubMedCrossRefGoogle Scholar
  37. Di Minno G, Davì G, Margaglione M, Cirillo F, Grandone E, Ciabattoni G, et al. 1993. Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism. J Clin Invest 92: 1400–1406.CrossRefGoogle Scholar
  38. Durand P, Prost M, Blache D, 1996. Pro-thrombotic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis 121: 231–243.PubMedCrossRefGoogle Scholar
  39. Durand P, Lussier-Cacan S, Blache D, 1997. Acute methionine load induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB Lett. 11: 1157–1168.Google Scholar
  40. Durand P, Prost M, Loreau N, Lussier-Cacan S, Blache D, 2001. Impaired homocysteine metabolism and atherothrombotic disease. Lab Invest 81: 645–672.PubMedCrossRefGoogle Scholar
  41. Eldibany MM, Caprini JA, 2007. Hyperhomocysteinemia and thrombosis: an overview. Arch Pathol Lab Med 131: 872–884.PubMedGoogle Scholar
  42. Engbersen AM, Franken DG, Boers GH, Stevens EM, Trijbels FJ, 1995. Thermolabile 5, 10-methyl-enetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 56: 142–150.PubMedGoogle Scholar
  43. Evans R, Shaten J, Hempel J, Cutler J, Kuller L, 1997. Homocyst(e)ine and risk of cardiovascular disease in the Multiple Risk Factor Intervention Trial. Arterioscler Thromb Vasc Biol 17: 1947–1953.PubMedGoogle Scholar
  44. Fallon UB, Virtamo J, Young I, McMaster D, Ben-Shlomo Y, Wood N, et al. 2003. Homocysteine and cerebral infarction in Finnish male smokers. Stroke 34: 1359–1363.PubMedCrossRefGoogle Scholar
  45. Folsom AR, Nieto FJ, McGovern PG, Tsai MY, Malinow MR, Eckfeldt JH, et al. 1998. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins. Circulation 98: 204–210.PubMedGoogle Scholar
  46. Franco RF, Araujo AG, Guerreiro JF, Elion J, Zago MA, 1998. Analysis of the 677 C T mutation of the methylenetetrahydrofolate reductase gene in different ethnic groups. Thromb Haemost 79: 119–121.PubMedGoogle Scholar
  47. Franco RF, Morelli V, Lourenço D, Maffei FH, Tavella MH, Piccinato CE, et al. 1999. A second mutation in the methylenetetrahydrofolate reductase gene and the risk of venous thrombotic disease. Br J Haematol 105: 556–559.PubMedCrossRefGoogle Scholar
  48. Franken DG, Boers GH, Blom HJ, Cruysberg JR, Trijbels FJ, Hamel BC, 1996. Prevalence of familial mild hyperhomocysteinemia. Atherosclerosis 125: 71–80.PubMedCrossRefGoogle Scholar
  49. Frei B, 1999. On the role of vitamin C and other antioxidants in atherogenesis and vascular dysfunction. Proc Soc Exp Biol Med 222: 196–204.PubMedCrossRefGoogle Scholar
  50. Friedman G, Goldschmidt N, Friedlander Y, Ben-Yehuda A, Selhub J, Babaey S, et al. 1999. A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr 129: 1656–1661.PubMedGoogle Scholar
  51. Friso S, Girelli D, Trabetti E, Stranieri C, Olivieri O, Tinazzi E, et al. 2002. A1298C methylenetetrahydrofolate reductase mutation and coronary artery disease: relationships with C677T polymorphism and homocysteine/folate metabolism. Clin Exp Med 2: 7–12.PubMedCrossRefGoogle Scholar
  52. Fryer R, Wilson B, Gubler D, Fitzgerald L, Rodgers G, 1993. Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells. Arterioscler Thromb Vasc Biol 13: 405–410.Google Scholar
  53. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. 1995. Identification of a candidate genetic risk factor for vascular disease: a common mutation at the methylenetetrahydrofolate reductase locus. Nat Genet 10: 111–113.PubMedCrossRefGoogle Scholar
  54. Genest JJ Jr, McNamara JR, Upson B, Salem DN, Ordovas JM, Schaefer EJ, et al. 1991. Prevalence of familial hyperhomocyst(e)inemia in men with premature coronary artery disease. Arterioscler Thromb 11: 1129–1136.PubMedGoogle Scholar
  55. Girelli D, Friso S, Trabetti E, Olivieri O, Russo C, Pessotto R, et al. 1998. Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interaction. Blood 91: 4158–4163.PubMedGoogle Scholar
  56. Girelli D, Martinelli N, Pizzolo F, Friso S, Olivieri O, Stranieri C, et al. 2003. The interaction betweenMTHFR 677 C—>T genotype and folate status is a determinant of coronary atherosclerosis risk. J Nutr 133: 1281–1285.PubMedGoogle Scholar
  57. Goyette P, Christensen B, Rosenblatt DS, Rozen R, 1996. Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations inMTHFR. Am J Hum Genet 59: 1268–1275.PubMedGoogle Scholar
  58. Graham IM, Daly LE, Refsum HM, Robinson K, Brattström LE, Ueland PM, et al. 1997. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA 277: 1775–1781.PubMedCrossRefGoogle Scholar
  59. Guéant-Rodriguez RM, Juilliére Y, Candito M, Adjalla CE, Gibelin P, Herbeth B, et al. 2005. Association ofMTRR A66G polymorphism (but not ofMTHFR C677T and A1298C,MTR A2756G,TCN C776G) with homocysteine and coronary artery disease in the French population. Thromb Haemost 94: 510–515.PubMedGoogle Scholar
  60. Guenther BD, Sheppard CA, Tran P, Rozen R, Matthews RG, Ludwig ML, 1999. The structure and properties of methylenetetrahydrofolate reductase fromEscherichia coli suggest how folate ameliorates human hyperhomocysteinemia. Nat Struct Biol 6: 359–365.PubMedCrossRefGoogle Scholar
  61. Guttormsen AB, Ueland PM, Nesthus I, Nygĺrd O, Schneede J, Vollset SE, et al. 1996. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (≥40 mol/liter). The Hordaland homocysteine study. J Clin Invest 98: 2174–2183.PubMedCrossRefGoogle Scholar
  62. Hajjar KA, Mauri L, Jacovina AT, Zhong F, Mirza UA, Padovan JC, et al. 1998. Tissue plasminogen activator binding to the annexin II tail domain. J Biol Chem 273: 9987–9993.PubMedCrossRefGoogle Scholar
  63. Hankey GJ, Eikelboom JW, 1999. Homocysteine and vascular disease. Lancet 354: 407–413.PubMedCrossRefGoogle Scholar
  64. Harker L, Ross R, Slichter S, Scott C, 1976. Homocystine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest 58: 731–741.PubMedCrossRefGoogle Scholar
  65. Harker L, Harian J, Ross R, 1983. Effect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboons. Circ Res 53: 731–739.PubMedGoogle Scholar
  66. Harmon DL, Woodside JV, Yarnell JW, McMaster D, Young IS, McCrum EE, et al. 1996. The common ‘thermolabile’ variant of methylene tetrahydrofolate reductase is a major determinant of mild hyperhomocysteinaemia. QJM 89: 571–577.PubMedGoogle Scholar
  67. Harmon DL, Doyle RM, Meleady R, Doyle M, Shields DC, Barry R, et al. 1999. Genetic analysis of the thermolabile variant of 5, 10-methylenetetra-hydrofolate reductase as a risk factor for ischemic stroke. Arterioscler Thromb Vasc Biol 19: 208–211.PubMedGoogle Scholar
  68. Harpel P, Zhang X, Borth W, 1996. Homocysteine and hemostasis: pathogenetic mechanisms predisposing to thrombosis. J Nutr 126: 1285S-1289S.PubMedGoogle Scholar
  69. Homocysteine Studies Collaboration, 2002. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 288: 2015–2022.CrossRefGoogle Scholar
  70. Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, et al. 2000. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation 101: 1506–1511.PubMedGoogle Scholar
  71. Inbal A, Freimark D, Modan B, Chetrit A, Matetzky S, Rosenberg N, et al. 1999. Synergistic effects of prothrombotic polymorphisms and atherogenic factors on the risk of myocardial infarction in young males. Blood 93: 2186–2190.PubMedGoogle Scholar
  72. Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, et al. 1996. Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93: 7–9.PubMedGoogle Scholar
  73. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH, 1999. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 340: 1449–1454.PubMedCrossRefGoogle Scholar
  74. Jonasson TF, Hedner T, Hultberg B, Ohlin H, 2003. Hyperhomocysteinaemia is not associated with increased levels of asymmetric dimethylarginine in patients with ischaemic heart disease. Eur J Clin Invest 33: 543–549.PubMedCrossRefGoogle Scholar
  75. Kalita J, Srivastava R, Bansal V, Agarwal S, Misra UK, 2006. Methylenetetrahydrofolate reductase gene polymorphism in Indian stroke patients. Neurol India 54: 260–263.PubMedCrossRefGoogle Scholar
  76. Kanani PM, Sinkey CA, Browning RL, Allaman M, Knapp HR, Haynes WG, et al. 1999. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomocyst(e)inemia in humans. Circulation 100: 1161–1168.PubMedGoogle Scholar
  77. Kang SS, Zhou J, Wong PWK, Kowalisyn J, Strokosch G, 1988. Intermediate homo-cysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet 43: 414–421.PubMedGoogle Scholar
  78. Kang SS, Wong PW, Susmano A, Sora J, Norusis M, Ruggie N, 1991. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. Am J Hum Genet 48: 536–545.PubMedGoogle Scholar
  79. Kang SS, Wong PW, Malinow MR, 1992. Hyperhomocysteinemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 12: 279–298.PubMedCrossRefGoogle Scholar
  80. Kelly PJ, Shih VE, Kistler JP, Barron M, Lee H, Mandell R, et al. 2003. Low vitamin B6 but not homocyst(e)ine is associated with increased risk of stroke and transient ischemic attack in the era of folic acid grain fortification. Stroke 34: e5l-54.CrossRefGoogle Scholar
  81. Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG, et al. 2002. MTHFR Studies Collaboration Group. MTHFR 677C—>T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288: 2023–2031.PubMedCrossRefGoogle Scholar
  82. Kruit MC, van Buchem MA, Hofman PA, Bakkers JT, Terwindt GM, Ferrari MD, et al. 2004. Migraine as a risk factor for subclinical brain lesions. JAMA 291: 427–434.PubMedCrossRefGoogle Scholar
  83. Kullo IJ, Ding K, Boerwinkle E, Turner ST, Mosley TH Jr, Kardia SL, et al. 2006. Novel genomic loci influencing plasma homocysteine levels. Stroke 37: 1703–1709.PubMedCrossRefGoogle Scholar
  84. Laraqui A, Allami A, Carrié A, Raisonnier A, Coiffard AS, Benkouka F, et al. 2007. Relation between plasma homocysteine, gene polymorphisms of homocysteine metabolism-related enzymes, and angiographically proven coronary artery disease. Eur J Int Med 18: 474–483.CrossRefGoogle Scholar
  85. Lehmann M, Gottfries CG, Regland B, 1999. Identification of cognitive impairment in the elderly: homocysteine is an early marker. Dement Geriatr Cogn Disord 10: 12–20.PubMedCrossRefGoogle Scholar
  86. Lentz SR, Sadler JE, 1991. Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 88: 1906–1914.PubMedCrossRefGoogle Scholar
  87. Lentz SR, Sobey CG, Piegors DJ, Bhopatkar MY, Faraci FM, Malinow MR, et al. 1996. Vascular dysfunction in monkeys with diet-induced hyper-homocyst(e)inenia. J Clin Invest 98: 24–29.PubMedCrossRefGoogle Scholar
  88. Lentz SR, 2005. Mechanisms of homocysteine-induced atherothrombosis. J Thromb Haemost 3: 1646–1654.PubMedCrossRefGoogle Scholar
  89. Leoncini G, Pascale R, Signorello MG, 2003. Effects of homocysteine on L-arginine transport and nitric oxide formation in human platelets. Eur J Clin Invest 33: 713–719.PubMedCrossRefGoogle Scholar
  90. Li Z, Sun L, Zhang H, Liao Y, Wang D, Zhao B, et al. 2003. 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 34: 2085–2090.PubMedCrossRefGoogle Scholar
  91. Lopez OL, Jagust WJ, Dulberg C, Becker JT, DeKosky ST, Fitzpatrick A, et al. 2003. Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study. Arch Neurol 60: 1394–1399.PubMedCrossRefGoogle Scholar
  92. Majors A, Ehrhart L, Pezacka E, 1997. Homocysteine as a risk factor for vascular disease. Enhanced collagen production and accumulation by smooth muscle cells. Arterioscler Thromb Vasc Biol 17: 2074–2081.PubMedGoogle Scholar
  93. Malinow M, Nieto F, Szklo M, Chambless L, Bond G, 1993. Carotid artery intimal-medial wall thickening and plasma homocyst(e)ine in asymptomatic adults. Circulation 87: 1107–1113.PubMedGoogle Scholar
  94. McCaddon A, Davies G, Hudson P, Tandy S, Cattell H, 1998. Total serum homocysteine in senile dementia of Alzheimer type. Int J Geriatr Psychiatry 13: 235–239.PubMedCrossRefGoogle Scholar
  95. McCaddon A, Hudson P, Davies G, Hughes A, Williams JH, Wilkinson C, et al. 2001. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord 12: 309–313.PubMedCrossRefGoogle Scholar
  96. McCully KS, 1969. Vascular pathology of homo-cysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56: 111–128.PubMedGoogle Scholar
  97. McCully KS, Ragsdale BD, 1970. Production of arteriosclerosis by homocysteinemia. Am J Pathol 61: 1–11.PubMedGoogle Scholar
  98. McCully KS, Wilson RB, 1975. Homocysteine theory of arteriosclerosis. Atherosclerosis 22: 215–227.PubMedCrossRefGoogle Scholar
  99. Moat SJ, Lang D, McDowell IF, Clarke ZL, Madhavan AK, Lewis MJ, et al. 2004. Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem 15: 64–79.PubMedCrossRefGoogle Scholar
  100. Morita H, Kurihara H, Tsubaki S, Sugiyama T, Hamada C, Kurihara Y, et al. 1998. Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese. Arterioscler Thromb Vasc Biol 18: 1465–1469.PubMedGoogle Scholar
  101. Mudd SH, Levy HL, Skovby F, 1995. Disorders of transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. 7th ed. New York, NY: McGraw-Hill 1279–1327.Google Scholar
  102. Mudd SH, Levy HL, Kraus J, 2001. Disorders of Transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Kinzler K, Vogelstein B, eds. The metabolic and molecular bases of inherited diseases. Mc Grow Hill 2007–2056.Google Scholar
  103. Nishinaga M, Ozawa T, Shimada K, 1993. Homocysteine, a thrombogenic agent, suppresses anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. J Clin Invest 92: 1381–1386.PubMedCrossRefGoogle Scholar
  104. Nygard O, Refsum H, Ueland PM, Stensvold I, Nordrehaug JE, Kvĺle G, et al. 1997a. Coffee consumption and total plasma homocysteine: the Hordland Homocysteine Study. Am J Clin Nutr 65: 136–143.PubMedGoogle Scholar
  105. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE, et al. 1997b. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1337: 230–236.CrossRefGoogle Scholar
  106. Nygard O, Refsum H, Ueland PM, Vollset SE, 1998. Major lifestyle determinants of plasma total homocysteine distribution: the Hordland Homocysteine Study. Am J Clin Nutr 67: 263–270.PubMedGoogle Scholar
  107. Nurk E, Tell GS, Vollset SE, Nygĺrd O, Refsum H, Ueland PM, et al. 2002. Plasma total homocysteine and hospitalizations for cardiovascular disease: the Hordaland Homocysteine Study. Arch Intern Med 162: 1374–1381.PubMedCrossRefGoogle Scholar
  108. Oikawa S, Murakami K, Kawanishi S, 2003. Oxidative damage to cellular and isolated DNA by homocysteine: implications for carcinogenesis. Oncogene 22: 3530–3538.PubMedCrossRefGoogle Scholar
  109. Olivieri O, Friso S, Trabetti E, Girelli D, Pizzolo F, Faccini G, et al. 2001. Homocysteine and atheromatous renal artery stenosis. Clin Exp Med 1: 211–218.PubMedCrossRefGoogle Scholar
  110. Papa A, De Stefano V, Danese S, Chiusolo P, Persichilli S, Casorelli I, et al. 2001. Hyperhomo-cysteinemia and prevalence of polymorphisms of homocysteine metabolism-related enzymes in patients with inflammatory bowel disease. Am J Gastroenterol 96: 2677–2682.PubMedCrossRefGoogle Scholar
  111. Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG, 1995. Prospective study of serum total homocysteine concentration and risk of stroke in middle-age British men. Lancet 346: 1395–1398.PubMedCrossRefGoogle Scholar
  112. Pezzini A, Del Zotto E, Archetti S, Negrini R, Bani P, Albertini A, et al. 2002. Plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke. Stroke 33: 664–669.PubMedCrossRefGoogle Scholar
  113. Pezzini A, Grassi M, Del Zotto E, Archetti S, Spezi R, Vergani V, et al. 2005. Cumulative effect of predisposing genotypes and their interaction with modifiable factors on the risk of ischemic stroke in young adults. Stroke 36: 533–539.PubMedCrossRefGoogle Scholar
  114. Pizzolo F, Friso S, Olivieri O, Martinelli N, Bozzini C, Guarini P, et al. 2006. Homocysteine, traditional risk factors and impaired renal function in coronary artery disease. Eur J Clin Invest 36: 698–704.PubMedCrossRefGoogle Scholar
  115. Poddar R, Sivasubramanian N, Dibello PM, Robinson K, Jacobsen DW, 2001. Homocysteine induces expression secretion of monocyte chemoattractant protein-1 and interleukin-8 in human aortic endothelial cells: implications for vascular disease. Circulation 103: 2717–2723.PubMedGoogle Scholar
  116. Ratnoff OD, 1968. Activation of Hageman factor by L-homocystine. Science 162: 1007–1009.PubMedCrossRefGoogle Scholar
  117. Reed T, Malinow MR, Christian JC, Upson B, 1991. Estimates of heritability of plasma homocyst(e)ine levels in aging adult male twins. Clin Genet 39: 425–428.PubMedCrossRefGoogle Scholar
  118. Refsum H, Ueland PM, Nygard O, Vollset SE, 1998. Homocysteine and cardiovascular disease. Annu Rev Med 49: 31–62.PubMedCrossRefGoogle Scholar
  119. Rezvani I, 2002. Metionina. in Nelson: Trattato di Pediatria. Edizioni Minerva Medica XVI Ed. X-82.3: 350–352.Google Scholar
  120. Robinson K, Mayer EL, Miller DP, Green R, van Lente F, Gupta A, et al. 1995. Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease. Circulation 92: 2825–2830.PubMedGoogle Scholar
  121. Rodgers G, Conn M, 1990. Homocysteine, an atherogenic stimulus, reduces protein C activation by arterial and venous endothelial cells. Blood 75: 895–901.PubMedGoogle Scholar
  122. Ross R, 1999. Atherosclerosis: an inflammatory disease. N Engl J Med 340: 115–126.PubMedCrossRefGoogle Scholar
  123. Rozen R, 1997. Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetra-hydrofolate reductase (MTHFR). Thromb Haemost 77: 523–526.Google Scholar
  124. Rozen R, 2000. Genetic modulation of homo-cysteinemia. Semin Thromb Hemost 26: 255–261.PubMedCrossRefGoogle Scholar
  125. Sacher Y, Soroker N, Motin M, Treger I, Ring H, Sela BA, et al. 2003. Blood homocysteine levels in stroke patients undergoing rehabilitation. Med Sci Monit 9: CR201–207.PubMedGoogle Scholar
  126. Salomon O, Steinberg DM, Zivelin A, Gitel S, Dardik R, Rosenberg N, et al. 1999. Single and combined prothrombotic factors in patients with idiopathic venous thromboembolism: prevalence and risk assessment. Arterioscler Thromb Vasc Biol 19: 511–518.PubMedGoogle Scholar
  127. Sazci A, Ergul E, Tuncer N, Akpinar G, Kara I, 2006. Methylenetetrahydrofolate reductase gene polymorphisms are associated with ischemic and hemorrhagic stroke: dual effect of MTHFR polymorphisms C677T and A1298C. Brain Res Bull 71: 45–50.PubMedCrossRefGoogle Scholar
  128. Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ, 2005. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 64: 614–620.PubMedGoogle Scholar
  129. Scher AI, Terwindt GM, Verschuren WM, Kruit MC, Blom HJ, Kowa H, et al. 2006. Migraine and MTHFR C677T genotype in a population-based sample. Ann Neurol 59: 372–375.PubMedCrossRefGoogle Scholar
  130. Schneider JA, Rees DC, Liu YT, Clegg JB, 1998. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet 62: 1258–1260.PubMedCrossRefGoogle Scholar
  131. Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM, 2002. Association of plasma homocysteine with restenosis after percutaneous coronary angioplasty. Eur Heart J 23: 726–733.PubMedCrossRefGoogle Scholar
  132. Selhub J, Jacques PF, Bostom AG, D’Agostino RB, Wilson PW, Belanger AJ, et al. 1995. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 332: 286–291.PubMedCrossRefGoogle Scholar
  133. Sengul E, Cetinarslan B, Tarku I, Canturk Z, Turemen E, 2004. Homocysteine concentrations in subclinical hypothyroidism. Endocr Res 3: 351–359.CrossRefGoogle Scholar
  134. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, et al. 2002. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346: 476–483.PubMedCrossRefGoogle Scholar
  135. Sharma P, Senthilkumar RD, Brahmachari V, Sundaramoorthy E, Mahajan A, Sharma A, et al. 2006. Mining literature for a comprehensive pathway analysis: a case study for retrieval of homocysteine related genes for genetic and epigenetic studies. Lipids Health Dis 5: 1.PubMedCrossRefGoogle Scholar
  136. Singal R, Ferdinand L, Das PM, Reis IM, Schlesselman JJ, et al. 2004. Polymorphisms in the methylenetetrahydrofolate reductase gene and prostate cancer risk. Int J Oncol 25: 1465–1471.PubMedGoogle Scholar
  137. Soriente L, Coppola A, Madonna P, Cerbone AM, Di Minno G, Orefice G, et al. 1998. Homozygous C677T mutation of the 5,10-methyl-enetetrahydrofolate reductase gene and hyperhomocysteinemia in Italian patients with a history of early-onset ischemic stroke. Stroke 29: 869–871.PubMedGoogle Scholar
  138. Spence JD, Bang H, Chambless LE, Stampfer MJ, 2005. Vitamin Intervention For Stroke Prevention trial: an efficacy analysis. Stroke 36: 2404–2409.PubMedCrossRefGoogle Scholar
  139. Stamler JS, Loscallzo J, 1992. Endothelium-derived relaxing factor modulates the atherothrombogenic effects of homocysteine. J Cardiol Pharmacol 20 suppl 12:s 202–204.Google Scholar
  140. Stamler JS, Osborne JA, Jaraki O, Rabbani LE, Mullins M, Singel D, et al. 1993. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 91: 308–318.PubMedCrossRefGoogle Scholar
  141. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, et al. 1992. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA 268: 877–881.PubMedCrossRefGoogle Scholar
  142. Starkekbaum G, Harlan J, 1986. Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 77: 1370–1376.CrossRefGoogle Scholar
  143. Stubbs PJ, Al-Obaidi MK, Conroy RM, Collinson PO, Graham IM, Noble IM, et al. 2000. Effect of plasma homocysteine concentration on early and late events in patients with acute coronary syndromes. Circulation 102: 605–610.PubMedGoogle Scholar
  144. Stühlinger MC, Oka RK, Graf EE, Schmölzer I, Upson BM, Kapoor O, et al. 2003. Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation 108: 933–938.PubMedCrossRefGoogle Scholar
  145. Su SJ, Huang LW, Pai LS, Liu HW, Chang KL, 2005. Homocysteine at pathophysiological concentrations activates human monocyte and induces cytokine expression and inhibits macrophage migration inhibitory factor expression. Nutrition 21: 994–1002.PubMedCrossRefGoogle Scholar
  146. Szczeklik A, Sanak M, Jankowski M, Dropiński J, Czachór R, Musiał J, et al. 2001. Mutation A1298C methylenetetrahydrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia. Am J Med Genet 101: 36–39.PubMedCrossRefGoogle Scholar
  147. Szolnoki Z, Somogyvari F, Szabo M, Kondacs A, Fodor L, Melegh B, 2006. Interactions between theMTHFR C677T andMTHFR A1298C mutations in ischaemic stroke, Ideggyogy Sz 59: 107–112.PubMedGoogle Scholar
  148. Tosetto A, Rodeghiero F, Martinelli I, De Stefano V, Missiaglia E, Chiusolo P, et al. 1998. Additional genetic risk factors for venous thromboembolism in carriers of the factor V Leiden mutation. Br J Haematol 103: 871–876.PubMedCrossRefGoogle Scholar
  149. Tsai JC, Perrella MA, Yoshizumi M, Hsieh CM, Haber E, Schlegel R, et al. 1994. Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci USA 91: 6369–6373.PubMedCrossRefGoogle Scholar
  150. Ubbink JB, Fehily AM, Pickering J, Elwood PC, Vermaak WJ, 1998. Homocysteine and ischaemic heart disease in the Caerphilly cohort. Atherosclerosis 140: 349–356.PubMedCrossRefGoogle Scholar
  151. Ueland PM, Refsum H, Brattström L, 1992. Plasma homocysteine and cardiovascular disease. In: Francis RB Jr, ed. Atherosclerotic cardiovascular disease, hemostasis and endothelial function. New York, NY: Marcel Dekker Inc 183–236.Google Scholar
  152. Ueland PM, Refsum H, Beresford SAA, Vollset SE, 2000. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr 72: 324–332.PubMedGoogle Scholar
  153. Ueland PM, Nygard O, Vollset SE, Refsum H, 2001. The Hordaland Homocysteine Studies. Lipids 36 Suppl: S33–39.PubMedCrossRefGoogle Scholar
  154. Upchurch GJ, Welch G, Loscalzo J, 1996. Homocysteine EDRF and endothelial function. J Nutr 126: 1290S-1294S.PubMedGoogle Scholar
  155. Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, et al. 1997. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 272: 17012–17017.PubMedCrossRefGoogle Scholar
  156. van der Gaag MS, Ubbink JB, Sillanaukee P, Nikkari S, Hendriks HF, 2000. Effect of consumption of red wine, spirits, and beer on serum homocysteine. Lancet 355: 1522.CrossRefGoogle Scholar
  157. van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, et al. 1998. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? Am J Hum Genet 62: 1044–1051.CrossRefGoogle Scholar
  158. Visioli F, Smith A, Zhang W, Keaney JF Jr, Hagen T, Frei B, et al. 2002. Lipoic acid and vitamin C potentiate nitric oxide synthesis in human aortic endothelial cells independently of cellular glutathione status. Redox Rep 7: 223–227.PubMedCrossRefGoogle Scholar
  159. Vollset SE, Refsum H, Tverdal A, Nygard O, Nordrehaug JE, Tell GS, et al. 2001. Plasma total homocysteine and cardiovascular and non-cardiovascular mortality: the Hordaland Homocysteine Study. Am J Clin Nutr 74: 130–136.PubMedGoogle Scholar
  160. Voutilainen S, Alfthan G, Nyyssonen K, Salonen R, Salonen J, 1998. Association between elevated plasma total homocysteine and increased common carotid artery wall thickness. Ann Med 30: 300–306.PubMedCrossRefGoogle Scholar
  161. Wald DS, Law M, Morris JK, 2002. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325: 1202–206.PubMedCrossRefGoogle Scholar
  162. Wanby P, Brattstrom L, Brudin L, Hultberg B, Teerlink T, 2003. Asymmetric dimethylarginine and total homocysteine in plasma after oral methionine loading. Scand J Clin Lab Invest 63: 347–353.PubMedCrossRefGoogle Scholar
  163. Wang H, Yoshizumi M, Lai K, Tsai JC, Perrella MA, Haber E, et al. 1997. Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine. J Biol Chem 272: 25380–25385.PubMedCrossRefGoogle Scholar
  164. Wang G, O K, 2001. Homocysteine stimulates the expression of monocyte chemoattractant protein-1 receptor (CCR2) in human monocytes: possible involvement of oxygen-free radicals. Biochem J 357: 233–240.PubMedCrossRefGoogle Scholar
  165. Wang G, Siow YL, O K, 2001. Homocysteine induces monocyte chemoattractant protein-1 expression by activating NF-kappa B in THP-1 macrophages. Am J Physiol Heart Circ Physiol 280: H2840–2847.PubMedGoogle Scholar
  166. Welch GN, Upchurch GR Jr, Loscalzo J, 1997. Homocysteine, oxidative stress and vascular disease. Hosp Pract (Minneap) 32: 81–82, 85, 88–92.Google Scholar
  167. Wilcken DE, Wilcken B, 1976. The pathogenesis of coronary artery disease. A possible role for methionine metabolism. J Clin Invest 57: 1079–1082.PubMedCrossRefGoogle Scholar
  168. Wu LL, Wu J, Hunt SC, James BC, Vincent GM, Williams RR, et al. 1994. Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem 40: 552–561.PubMedGoogle Scholar
  169. Wu LL, Wu JT, 2002. Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker. Clin Chim Acta 322: 21–28.PubMedCrossRefGoogle Scholar
  170. Zetterberg H, Rymo L, Coppola A, D’Angelo A, Spandidos DA, Blennow K, 2002.MTHFR C677T and A1298C polymorphisms and mutated sequences occurring in cis. Eur J Hum Genet 10: 579–582.CrossRefGoogle Scholar
  171. Zetterberg H, Coppala A, D’Angelo A, Palmér M, Rymo L, Blennow K, 2003. No association between theMTHFR A1298C and transcobalamin C776G genetic polymorphisms and hyper-homocysteinemia in thrombotic disease. Thromb Res 108: 127–131.CrossRefGoogle Scholar
  172. Zhu BT, 2003. Medical hypothesis: hyperhomocysteinemia is a risk factor for estrogen-induced hormonal cancer. Int J Oncol 22: 499–508.PubMedGoogle Scholar

Copyright information

© Institute of Plant Genetics, Polish Academy of Sciences, Poznan 2008

Authors and Affiliations

  1. 1.Department of Mother and Child and Biology-Genetics, Section of Biology and GeneticsUniversity of VeronaVeronaItaly

Personalised recommendations