The MTHFR C677T polymorphism confers a high risk for stroke in both homozygous and heterozygous T allele carriers with Type 2 diabetes

Diabetic Medicine

Volumn 23, Issue 5, 2006, Pages 529-536

  Hermans, M P ^a   Gala, J L ^a,b   Buysschaert, M ^a  

^a CLINIQUES UNIVERSITAIRES SAINT LUC   (Belgium)

^b Belgian Ministry of Defense   (Belgium)

Author keywords

Diabetes; Folate; Homocysteine; MTHFR; Stroke

Indexed keywords

5,10 METHYLENETETRAHYDROFOLATE REDUCTASE (FADH2); CYTOSINE; FOLIC ACID; HOMOCYSTEINE; THYMINE; VITAMIN; CYANOCOBALAMIN; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2);

AGED; ALLELE; AMINO ACID BLOOD LEVEL; ANALYTICAL ERROR; ARTERY DISEASE; ARTICLE; C ALLELE; CARDIOVASCULAR RISK; COHORT ANALYSIS; CONTROLLED STUDY; CORONARY ARTERY DISEASE; CT GENOTYPE; FEMALE; FOLIC ACID BLOOD LEVEL; GENE FREQUENCY; GENE MUTATION; GENETIC POLYMORPHISM; GENOTYPE; HETEROZYGOSITY; HETEROZYGOTE; HIGH RISK POPULATION; HOMOZYGOSITY; HUMAN; MAJOR CLINICAL STUDY; MALE; NON INSULIN DEPENDENT DIABETES MELLITUS; PHENOTYPE; PREVALENCE; STATISTICAL ANALYSIS; STROKE; T ALLELE; TT GENOTYPE; VITAMIN BLOOD LEVEL; BLOOD; CEREBROVASCULAR ACCIDENT; CORONARY ARTERY ATHEROSCLEROSIS; DIABETIC ANGIOPATHY; GENETICS; HOMOZYGOTE; MUTATION; PERIPHERAL VASCULAR DISEASE; RISK FACTOR;

AGED; CEREBROVASCULAR ACCIDENT; COHORT STUDIES; CORONARY ARTERIOSCLEROSIS; DIABETES MELLITUS, TYPE 2; DIABETIC ANGIOPATHIES; FEMALE; FOLIC ACID; GENE FREQUENCY; HETEROZYGOTE; HOMOZYGOTE; HUMANS; MALE; METHYLENETETRAHYDROFOLATE REDUCTASE (NADPH2); MUTATION; PERIPHERAL VASCULAR DISEASES; POLYMORPHISM, GENETIC; RISK FACTORS; VITAMIN B 12;

EID: 33645968711     PISSN: 07423071     EISSN: 14645491     Source Type: Journal    
DOI: 10.1111/j.1464-5491.2006.01841.x     Document Type: Article

References (53)

1. Manson JE Colditz GA Stampfer MJ Willett WC Krolewski AS Rosner B et al. A prospective study of maturity-onset diabetes mellitus and risk of coronary heart disease and stroke in women Arch Intern Med 1991 151 1141 1147
2. Stamler J Vaccaro O Neaton JD Wentworth D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial Diabetes Care 1993 16 434 444
3. Kothari V Stevens RJ Adler AI Stratton IM Manley SE Neil HA et al. UKPDS 60: risk of stroke in type 2 diabetes estimated by the UK Prospective Diabetes Study risk engine Stroke 2002 33 1776 1781
4. Boushey C Beresford S Omenn G Motulsky A. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes J Am Med Assoc 1996 274 1049 1057
5. Munshi M Stone A Fink L Fonseca V. Hyperhomocysteinaemia following a methionine load in patients with non-insulin-dependent diabetes mellitus and macrovascular disease Metabolism 1996 45 133 135
6. Nygärd O Nordrehaug JE Refsum H Ueland PE Farstad M Vollset SE Plasma homocysteine levels and mortality in patients with coronary artery disease N Engl J Med 1997 337 230 236
7. Hoogeveen EK Kostense PJ Beks PJ Mackaay AJ Jakobs C Bouter LM et al. Hyperhomocysteinaemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus: a population-based study Arterioscl Thromb Vasc Biol 1998 18 133 138
8. Okada E Oida K Tada H Asazuma K Eguchi K Tohda G et al. Hyperhomocysteinemia is a risk factor for coronary arteriosclerosis in Japanese patients with type 2 diabetes Diabetes Care 1999 22 484 490
9. Hoogeveen EK Kostense PJ Jakobs C Dekker JM Nijpels G Heine RJ et al. Hyperhomocysteinaemia increases risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn study Circulation 2000 101 1506 1511
10. Becker A Kostense PJ Bos G Heine RJ Dekker JM Nijpels G et al. Hyperhomocysteinaemia is associated with coronary events in type 2 diabetes J Int Med 2003 253 293 300
11. Buysschaert M Gala JL Hermans MP L'homocystéinémie: un marqueur essentiel en pathologie endocrinienne, aussi In Guéritée N Leclère J eds Mises Au Point Cliniques D'endocrinologie, Nutrition et Métabolisme Paris Les Editions de Médecine Pratique 2003 23 169 180
12. Buysschaert M Hermans MP Comment je traite et prends en charge une hyperhomocystéinémie In Selam JL ed Journées de Diabétologie Hôtel-Dieu 2003 Paris Flammarion Médecine Sciences 2003 42 229 237
13. De Koning L Werstuck G Zhou J Austin RC Hyperhomocysteinemia and its role in the development of atherosclerosis Clin Biochem 2003 36 431 441
14. Soinio M Marniemi J Laakso M Lehto S Ronnemaa T Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus Ann Intern Med 2004 140 94 100
15. Welch GN Loscalzo J. Homocysteine and atherothrombosis N Engl J Med 1998 338 1042 1050
16. Stanger O Herrmann W Pietrzik K Fowler B Geisel J Dierkes J et al. DACH-LIGA Homocystein (German, Austrian and Swiss Homocysteine Society): Consensus paper on the rational clinical use of homocysteine, folic acid and B-vitamins in cardiovascular and thrombotic diseases Clin Chem Lab Med 2003 41 1392 1403
17. Geisel J Hubner U Bodis M Schorr H Knapp JP Obeid R et al. The role of genetic factors in the development of hyperhomocysteinemia Clin Chem Lab Med 2003 41 1427 1434
18. 677T methylene-tetrahydrofolate reductase mutation in type 2 diabetic patients with and without hyperhomocysteinaemia Diabetes Metab 2004 30 349 354
19. Casas JP Bautista LE Smeeth L Sharma P Hingorani AD Homocysteine and stroke: evidence on a causal link from mendelian randomisation Lancet 2005 365 224 232
20. Frosst P Blom HJ Milos R Goyette P Sheppard CA Matthews RG et al. A candidate genetic risk factor for vascular disease: a common mutation in methyletetrahydrofolate reductase Nat Gen 1995 10 111 113
21. 677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease Blood 1998 91 4158 4163
22. Födinger M Hörl WH Sunder-Plassmann G. Molecular biology of 5,10-methylenetetrahydrofolate reductase J Nephrol 1999 13 1 17
23. Fodinger M Mannhalter C Wolfl G Pabinger I Muller E Schmid R et al. Mutation (677C → T) in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteinemia in hemodialysis patients Kidney Int 1997 52 517 523
24. Lim PS Hung WR Wei YH Polymorphism in methylenetetrahydrofolate reductase gene: its impact on plasma homocysteine levels and carotid atherosclerosis in ESRD patients receiving hemodialysis Nephron 2001 87 249 256
25. Buysschaert M Dramais AS Wallemacq PE Hermans MP Hyperhomocysteinaemia in type 2 diabetes. Relationship to macroangiopathy, nephropathy, and insulin resistance Diabetes Care 2000 23 1816 1822
26. Kang SS Wong PW Malinow MR Hyperhomocyst(e)inaemia is a risk factor for occlusive vascular disease Ann Rev Nutr 1992 12 279 298
27. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report Diabetes Care 1997 20 1183 1197
28. The Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults Third report. Available from:
29. UK Prospective Diabetes Study (UKPDS). VIII. Study design, progress and performance Diabetologia 1991 34 877 890
30. Buysschaert M Jamart J Dramais AS Wallemacq P Hermans MP Micro- and macrovascular complications and hyperhomocysteinaemia in type 1 diabetic patients Diabetes Metab 2001 27 655 659
31. Hermans MP Levy JC Morris RJ Turner RC Comparison of tests of β-cell function across a range of glucose tolerance from normal to diabetes Diabetes 1999 48 1779 1786
32. OMIM'. Online Mendelian inheritance in man. Available from:
33. Szolnoki Z Somogyvari F Kondacs A Szabo M Fodor L Bene J et al. Evaluation of the modifying effects of unfavourable genotypes on classical clinical risk factors for ischaemic stroke J Neurol Neurosurg Psychiatry 2003 74 1615 1620
34. 677T mutations and events of the arterial circulatory system: a meta-analysis of published studies Am Heart J 2003 146 948 957
35. Kissela BM Khoury J Kleindorfer D Woo D Schneider A Alwell K et al. Epidemiology of ischemic stroke in patients with diabetes: the greater Cincinnati/Northern Kentucky Stroke Study Diabetes Care 2005 28 355 359
36. Fonseca V Guba SC Fink LM Hyperhomocysteinemia and the endocrine system: implications for atherosclerosis and thrombosis Endocr Rev 1999 20 738 759
37. Chango A Boisson F Barbe F Quilliot D Droesch S Pfister M et al. The effect of 677C → T and 1298A → C mutations on plasma homocysteine and 5,10-methylenetetrahydrofolate reductase activity in healthy subjects Br J Nutr 2000 83 593 596
38. Meleady R Ueland PM Blom H Whitehead AS Refsum H Daly LE et al. Thermolabile methylenetetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: the European Concerted Action Project Am J Clin Nutr 2003 77 63 70
39. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis J Am Med Assoc 2002 288 2015 2022
40. Klerk M Verhoef P Clarke R Blom HJ Kok FJ Schouten EG MTHFR Studies Collaboration Group. MTHFR 677C → T polymorphism and risk of coronary heart disease: a meta-analysis J Am Med Assoc 2002 288 2023 2031
41. Geisel J Hennen B Hubner U Knapp JP Herrmann W. The impact of hyperhomocysteinemia as a cardiovascular risk factor in the prediction of coronary heart disease Clin Chem Lab Med 2003 41 1513 1517
42. de Bree A Verschuren WM Bjorke-Monsen AL van der Put NM Heil SG Trijbels FJ et al. Effect of the methylenetetrahydrofolate reductase 677C → T mutation on the relations among folate intake and plasma folate and homocysteine concentrations in a general population sample Am J Clin Nutr 2003 77 687 693
43. Kluijtmans LA Young IS Boreham CA Murray L McMaster D McNulty H et al. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults Blood 2003 101 2483 2488
44. Stanger O Weger M. Interactions of homocysteine, nitric oxide, folate and radicals in the progressively damaged endothelium Clin Chem Lab Med 2003 41 1444 1454
45. Aso Y Okumura K Yoshida N Tayama K Kanda T Kobayashi I et al. Plasma interleukin-6 is associated with coagulation in poorly controlled patients with Type 2 diabetes Diabet Med 2003 20 930 934
46. Selhub J Bagley LC Miller J Rosenberg IH B vitamins, homocysteine, and neurocognitive function in the elderly Am J Clin Nutr 2000 71 614S 620S
47. Mutus B Rabini RA Staffolani R Ricciotti R Fumelli P Moretti N et al. Homocysteine-induced inhibition of nitric oxide production in platelets: a study on healthy and diabetic subjects Diabetologia 2001 44 979 982
48. 677T polymorphism and its relation to ischemic stroke in the Black Sea Turkish population Am J Hematol 2004 76 40 43
49. 677T polymorphism was a risk factor for thrombotic stroke Stroke 2003 34 2085 2090
50. Kohara K Fujisawa M Ando F Tabara Y Niino N Miki T et al. MTHFR gene polymorphism as a risk factor for silent brain infarcts and white matter lesions in the Japanese general population: The NILS-LSA Study Stroke 2003 34 1130 1135
51. 677T common variant on hypertensive risk is not solely explained by increased plasma homocysteine values Clin Exp Hypertens 2003 25 209 220
52. Stehouwer CD van Guldener C. Does homocysteine cause hypertension? Clin Chem Lab Med 2003 41 1408 1411
53. Kelly PJ Rosand J Kistler JP Shih VE Silveira S Plomaritoglou A et al. Homocysteine, MTHFR 677C → T polymorphism, and risk of ischemic stroke: results of a meta-analysis Neurology 2002 59 529 536