Journal of Endocrinological Investigation

, Volume 29, Issue 9, pp 814–820

Methylenetetrahydrofolate reductase gene polymorphism, homocysteine and risk of macroangiopathy in Type 2 diabetes mellitus

Original Articles


Objective: A polymorphism in the gene for methylenetetrahydrofolate reductase (MTHFR) has been reported to be associated with hyperhomocysteinemia and risk for atherosclerotic vascular diseases. In this case-control study, we examined the distribution of the MTHFR genotypes in the Chinese population and clarified the relationship between the gene polymorphism for MTHFR and macroangiopathy in Chinese Type 2 diabetes mellitus. Methods: Two hundred and sixteen unrelated patients with Type 2 diabetes mellitus, 112 of whom had macroangiopathy, and 114 healthy control subjects, were recruited. The MTHFR C677T genotype was analyzed by polymerase chain reaction-restriction fragment length polymorphism. Plasma total homocysteine levels were measured using high-performance liquid chromatography (HPLC) with fluorescence detection. Results: In 114 healthy control subjects, the frequency of the mutant T allele was 31.1%. The genotype distribution did not differ between control subjects and Type 2 diabetic patients (χ2=3.03, p=0.220). Genotypic analysis revealed that the MTHFR genotype was different between diabetic patients with and without macroangiopathy (χ2=12.42, p=0.002). Type 2 diabetic patients with macroangiopathy displayed a greater prevalence of T allele than Type 2 diabetic patients without macroangiopathy (44.6 vs 29.3%; χ2=10.82, p=0.001). The odds ratio for macroangiopathy in Type 2 diabetic patients in presence of T allele was 1.94 [confidence interval (CI) 95%: 1.31–2.89]. Moreover, plasma homocysteine levels were markedly higher in individuals with TT genotype than those with CC or CT genotype. Conclusions: The C677T mutation of MTHFR gene is common in the Chinese population. MTHFR C677T gene polymorphism associated with a predisposition to increased plasma homocysteine levels could constitute a useful predictive marker for macroangiopathy in Chinese Type 2 diabetic patients.


Genetics methylenetetrahydrofolate reductase Type 2 diabetes mellitus macroangiopathy homocysteine 


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  1. 1.
    Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999, 354: 407–13.PubMedCrossRefGoogle Scholar
  2. 2.
    Stehouwer CDA, Weijenberg MP, van den Berg M, Jakobs C, Feskens EJM, Kromhout D. Serum homocysteine and risk of coronary heart disease and cerebrovascular disease in elderly men: a 10-year follow-up. Arterioscler Thromb Vasc Biol 1998, 18: 1895–901.PubMedCrossRefGoogle Scholar
  3. 3.
    Frosst P, Bloom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995, 10: 111–3.PubMedCrossRefGoogle Scholar
  4. 4.
    Kluijtmans LAJ, Vanden LPWJ, Boers GHJ. Moleuclar genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 1996, 58: 35–41.PubMedCentralPubMedGoogle Scholar
  5. 5.
    Bockxmear FM, Mamolte CDS, Vasikaram SD. Methylenetrahydrofolate reductase gene and coronary heart disease. Circulation 1997, 95: 21–4.CrossRefGoogle Scholar
  6. 6.
    Agullo-Ortuno MT, Albaladejo MD, Parra S, et al. Plasmatic homocysteine concentration and its relationship with complications associated to diabetes mellitus. Clin Chim Acta 2002, 326: 105–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Hasegawa G, Obayashi H, Kamiuchi K, et al. The association between end-stage diabetic nephropathy and methylene-tetrahydrofolate reductase genotype with macroangiopathy in type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes 2003, 111: 132–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Araki A, Sako Y, Ito H. Plasma homocysteine concentrations in Japanese patients with non-insulin-dependent diabetes mellitus: Effect of parenteral methylcobalamin treatment. Atherosclerosis 1993, 103: 149–57.PubMedCrossRefGoogle Scholar
  9. 9.
    Jacobsen DW, Gatautis VJ, Green R. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem 1994, 40: 873–81.PubMedGoogle Scholar
  10. 10.
    Hoogeveen EK, Kostense PJ, Beks PJ, Mackaay AJC, Jakobs C. Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus a population-based study. Arterioscler Thromb Vasc Biol 1998, 18: 133–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Yeromenko Y, Lavie L, Levy Y. Homocysteine and cardiovascular risk in patients with diabetes mellitus. Nutr Metab Cardiovasc Dis 2001, 11: 108–16.PubMedGoogle Scholar
  12. 12.
    Audelin MC, Genest J. Homocysteine and cardiovascular disease in diabetes mellitus. Atherosclerosis 2001, 159: 497–511.PubMedCrossRefGoogle Scholar
  13. 13.
    Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet 1998, 62: 1258–60.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Smulders Y, Rakic M, Slaats E, et al. Fasting and post-methionine homocysteine levels in NIDDM: determinants and correlations with retinopathy, albuminuria, and cardiovascular disease. Diabetes Care 1999, 22: 125–32.PubMedCrossRefGoogle Scholar
  15. 15.
    Fujita H, Narita T, Meguro H, et al. No association between MTHFR gene polymorphism and diabetic nephropathy in Japanese type II diabetic patients with proliferative diabetic retinopathy. J Diabetes Complications 1999, 13: 284–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Helfenstein T, Fonsecaa FA, Revals WG, et al. Prevalence of myocardial infarction is related to hyperhomocysteinemia but not influenced by C677T methylenetetrahydrofolate reductase and A2756G methionine synthase polymorphisms in diabetic and non-diabetic subjects. Clin Chim Acta 2005, 355: 165–72.PubMedCrossRefGoogle Scholar
  17. 17.
    Scaglione L, Gambino R, Rolfo E, et al. Plasma homocysteine, methylenetetrahydrofolate reductase gene polymorphism and carotid intima-media thickness in Italian type 2 diabetic patients. Eur J Clin Invest 2002, 32: 24–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Gudnason V, Stansbie D, Scott J, et al. C677T polymorphism in methylenetetrahydrofolate reductase: its frequency and impact on plasma homocysteine concentration in different European populations. Atherosclerosis 1998, 136: 347–54.PubMedCrossRefGoogle Scholar
  19. 19.
    Pancharuniti N, Lewis CA, Sauserlich HE. Plasma homocysteine, folate, and vitamin B12 concentration and risk for early-onset coronary heart disease. Am J Clin Nutr 1994, 9: 940–8.Google Scholar
  20. 20.
    Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 1998, 64: 169–72.PubMedCrossRefGoogle Scholar
  21. 21.
    Kang SS, Wong PW. Genetic and nongenetic factors for moderate hyperhomocyst(e)inemia. Atherosclerosis 1996, 119: 135–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Jacques PF, Bostom AG, Williams RR, et al. Relation between folate status, a common mutation in methylene-tetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 1996, 93: 7–Google Scholar
  23. 23.
    Ma J, Stampfer MJ, Hennekens CH, et al. Methylenetetrahy-drofolate reductase polymorphism, plasma folate, homocysteine and risk of myocardial infarction in US physicians. Circulation 1996, 94: 2410–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Verhoef P, Kok FJ, Kluijtmans LA, et al. The 677CT mutation in the methylenetetrahydrofolate reductase gene: Associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease. Atherosclerosis 1997, 132: 105–13.PubMedCrossRefGoogle Scholar
  25. 25.
    Tokgozoglu SL, Alikasifoglu M, Unsal, et al. Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary heart disease in a population with low plasma folate. Heart 1999, 81: 518–22.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Mager A, Lalezari S, Shohat T, et al. Methylenetetrahydrofolate reductase genotypes and early-onset coronary heart disease. Circulation 1999,100: 2406–10.PubMedCrossRefGoogle Scholar
  27. 27.
    Šimon J, Mayer O, Rosolová H. The influence of folates, B12 vitamin and lifestyle factors in mild hyperhomocysteinemia in a population sample. Cas Lék Ces 1999, 21: 650–3.Google Scholar
  28. 28.
    Bostom AG, Shemin D, Lapane, K, et al. Hyperhomocysteinemia and traditional cardiovascular disease risk factors in end-stage renal disease patients on dialysis: a case-control study. Atherosclerosis 1995, 114: 93–103.PubMedCrossRefGoogle Scholar
  29. 29.
    Chauveau P, Chadefaux B, Coude M, et al. Hyperhomocysteinemia, a risk factor for atherosclerosis in chronic uremic patients. Kidney Int 1993, 41: 72–7.Google Scholar
  30. 30.
    Agardh CD, Agardh E, Andersson A, Hultberg B. Lack of association between plasma homocysteine levels and microangiopathy in type 1 diabetes mellitus. Scand J Clin Lab Invest 1994, 54: 637–41.PubMedCrossRefGoogle Scholar
  31. 31.
    Wollesen F, Brattstrom L, Refsum H, et al. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999, 55: 1028–35.PubMedCrossRefGoogle Scholar
  32. 32.
    Stabler S, Estacio R, Jeffers B, Cohen J, Allen R, Schrier R. Total homocysteine is associated with nephropathy in noninsulin-dependent diabetes mellitus. Metabolism 1999, 48: 1096–101.PubMedCrossRefGoogle Scholar
  33. 33.
    Hofmann MA, Kohl B, Zumbach MS, et al. Hyperhomocyst(e)inemia and endothelial dysfunction in IDDM. Diabetes Care 1997, 20: 1880–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Chico A, Perez A, Cordoba A, et al. Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease? Diabetologia 1998, 41: 684–93.PubMedCrossRefGoogle Scholar
  35. 35.
    Lanfredini M, Fiorina P, Peca MG, et al. Fasting and postmethionine load homocyst(e)ine values are correlated with microalbuminuria and could contribute to worsening vascular damage in non-insulin dependent diabetes mellitus patients. Metabolism 1998, 47: 915–21.PubMedCrossRefGoogle Scholar
  36. 36.
    Arruda VR, von-Zuben PM, Chiaparini LC, Annichino-Bizzacchi JM, Costa FF. The mutation Ala677-Val in the methylenetet-rahydrofolate reductase gene:a risk factor for arterial disease and venous thrombosis. Thromb Haemost 1997, 77: 818–21.PubMedGoogle Scholar
  37. 37.
    Outinen PA, Sood SK, Liaw PC, et al. Characterization of the stress-inducing effects of homocysteine. Biochem 1998, 332: 213–21.Google Scholar
  38. 38.
    Upchurch GRJ, Welch GN, Fabian AJ, et al. Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 1997, 272: 17012–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Landgren F., Isralsson B., Lindgren A. Plasma homocysteine in actue myocardial infarction: homocyteine-lowering effect of folic acid. J Intern Med 1995, 237: 381–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Naurath HJ, Joosten E, Riezler R. Effect of vitamin B12, folate and vitamin B6 supplements in elderly people with normal serum vitamin concentration. Lancet 1995, 346: 85–9.PubMedCrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2006

Authors and Affiliations

  1. 1.Department of Endocrinology, Zhongnan HospitalWuhan UniversityWuhanChina

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