Molecular Biology Reports

, Volume 37, Issue 1, pp 105–109 | Cite as

Methylenetetrahydrofolate reductase gene polymorphism in diabetes and obesity

  • Javad Tavakkoly Bazzaz
  • Mahnaz Shojapoor
  • Habibollah Nazem
  • Parvin Amiri
  • Hossein Fakhrzadeh
  • Ramin Heshmat
  • Maryam Parvizi
  • Shirin Hasani Ranjbar
  • Mahsa M. Amoli


Methylenetetrahydrofolate reductase (MTHFR) polymorphism may play an important role in the pathophysiology of obesity and diabetes accompanied by obesity due to its influence on plasma homocysteine levels. There are significant and sometimes very strong relationship between levels of homocysteine and several multi-system diseases including CHD and CVA. To examine the association between MTHFR gene C677T polymorphism in diabetes and obesity with serum homocysteine levels. A total of 682 subjects were recruited in four groups (Normal, obese, diabetic and obese and diabetics). MTHFR gene C677T polymorphism was detected using PCR-RFLP technique. Serum homocysteine levels were measured using HPLC. There was a significant increase in the mean serum homocysteine levels in subjects carrying TT genotype (34.6 ± 26.5) compared to subjects carrying CC (15.1 ± 8) or CT genotype (16.4 ± 7.8) (P < 0.000). We found no significant differences for MTHFR allele and genotype frequencies between different groups. Our data have confirmed the association between serum homocysteine levels and MTHFR C677T genotype reported in other populations.


MTHFR Polymorphism Homocysteine Diabetes Obesity 



This study was funded by Endocrinology and Metabolism Research center of Tehran University of Medical Sciences. We thank the head, academic and support staff and laboratory of EMRC.


  1. 1.
    Refsume H, Ueland PM (1998) Recent data are not in conflict with homocystein as a cardiovascular risk factor. Curr Opin Lipidol 9:533–539. doi: 10.1097/00041433-199812000-00004 CrossRefGoogle Scholar
  2. 2.
    Outinen PA, Sood SK, Liaw PC, Sarge KD, Maeda N, Hirsh J et al (1998) Characterization of the stress-inducing effects of homocysteine. Biochem J 332:213–221PubMedGoogle Scholar
  3. 3.
    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. doi: 10.1074/jbc.272.27.17012 CrossRefPubMedGoogle Scholar
  4. 4.
    Freitas AI, Mendonca I, Guerra G, Brion M, Reis RP, Carracedo A, Brehm A (2008) Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymprphism does matter. Inferences from a case study (Madeira, Portugal). Thromb Res 122:648–656. doi: 10.1016/j.thromres.2008.02.005 CrossRefPubMedGoogle Scholar
  5. 5.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthew RG et al (1995) A candidate genetic risk factors for vascular disease: a common mutation in methylenetetrahydrofolate reductase: isolation of Cdna, mapping and mutation identification. Nat Genet 10:110–113. doi: 10.1038/ng0595-111 CrossRefGoogle Scholar
  6. 6.
    Rassoul F, Richter V, Hentschel B, Geisel J, Herrmann W, Kuntze T (2008) Plasma homocysteine levels & 677C→T methylenetetrahydrofolate reductase gene polymorphism in patients with coronary artery disease of different severity. Indian J Med Res 127:154–158PubMedGoogle Scholar
  7. 7.
    Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG (2002) MTHFR studies collaboration group. MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA 288:2023–2031CrossRefPubMedGoogle Scholar
  8. 8.
    Inamoto N, Katsuya T, Kokubo Y, Mannami T, Asai T, Baba S et al (2003) Association of methylenetetrahydrofolate reductase gene polymorphism with carotid atherosclerosis depending on smoking status in a Japanese general population. Stroke 34:1628–1633. doi: 10.1161/01.STR.0000075769.09092.82 CrossRefPubMedGoogle Scholar
  9. 9.
    Ueland PM, Refsum H, Stabler SP, Malinow MR, Andersson A, Allen RH (1993) Total homocysteine in plasma and serum: methods and clinical applications. Clin Biochem 93:1764–1779Google Scholar
  10. 10.
    Guttormsen AB, Ueland PM, Nesthus I, Nygard O, Schneede J, Vollset S et al (1996) Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (equal to or greater than 40 micromole/liter): the Hordaland homocysteine study. J Clin Invest 98:2174–2183. doi: 10.1172/JCI119024 CrossRefPubMedGoogle Scholar
  11. 11.
    Frosst P, Zhang Z-X, Pai A, Rozen R (1996) The methylenetetrahydrofolate reductase (Mthfr) gene maps to distal mouse chromosome 4. Mamm Genome 7:864–869. doi: 10.1007/s003359900255 CrossRefPubMedGoogle Scholar
  12. 12.
    Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93:7–9PubMedGoogle Scholar
  13. 13.
    Thawnashom K, Tungtrongchitr R, Petmitr S, Pongpaew P, Phonrat B, Tungtrongchitr A, Schelp FP (2005) Methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) in relation to homocysteine concentration in overweight and obese Thais. Southeast Asian J Trop Med Public Health 36:459–466PubMedGoogle Scholar
  14. 14.
    Terruzzi I, Senesi P, Fermo I, Lattuada G, Luzi L (2007) Are genetic variants of the methyl group metabolism enzymes risk factors predisposing to obesity? J Endocrinol Invest 30:747–753PubMedGoogle Scholar
  15. 15.
    Song C, Xing D, Tan W, Wei Q, Lin D (2001) Methylenetetrahydrofolate reductase gene polymorphism increase risk of esophageal squamous cell carcinoma in a Chinese population. Cancer Res 61:3272–3275PubMedGoogle Scholar
  16. 16.
    Nygård O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE (1997) Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 337:230–236. doi: 10.1056/NEJM199707243370403 CrossRefPubMedGoogle Scholar
  17. 17.
    Molloy AM, Daly S, Mills JL et al (1997) Thermolabile variant of 5, 10-methylenetetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 349:1591–1593. doi: 10.1016/S0140-6736(96)12049-3 CrossRefPubMedGoogle Scholar
  18. 18.
    Ma J, Stampfer MJ, Giovannucci E et al (1997) Methylenetetrahydrofolate reductase polymorphism, dietary interactions and risk of colorectal cancer. Cancer Res 57:1098–1102PubMedGoogle Scholar
  19. 19.
    Ma J, Stampfer MJ, Christensen B et al (1999) A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 8:825–829PubMedGoogle Scholar
  20. 20.
    Gallisti S, Sudi k, Mangge H, Erwa W, Borkenstein M (2000) Insuline is an independent correlate of plasma homocusteine levels in obese children and adolescents. Diabetes Care 23:1348–1352. doi: 10.2337/diacare.23.9.1348 CrossRefGoogle Scholar
  21. 21.
    Ruiz JR, Hurtig-Wennlof A, Ortega FB, Patterson E, Nilsson TK et al (2007) Homocysteine levels in children and adolescents are associated with the methylenetetrahydrofolate reductase 677C>T genotype, but not with physical activity, fitness or fatness: the European youth heart study. Br J Nutr 97:255–262. doi: 10.1017/S0007114507280535 CrossRefPubMedGoogle Scholar
  22. 22.
    Nakai K, Itoh C, Nakai K, Habano W, Gurwitz D (2001) Correlation between C677T MTHFR gene polymorphism, plasma homocysteine levels and the incidence of CAD. Am J Cardiovasc Drugs 1:353–361. doi: 10.2165/00129784-200101050-00005 CrossRefPubMedGoogle Scholar
  23. 23.
    Virtanen JK, Voutilainen S, Alfthan G, Korhonen MJ, Rissanen TH, Mursu J, Kaplan GA, Salonen JT (2005) Homocysteine as a risk factor for CVD mortality in men with other CVD risk factors: the Kuopio ischaemic heart disease risk factor (KIHD) study. J Intern Med 257:255–262. doi: 10.1111/j.1365-2796.2005.01450.x CrossRefPubMedGoogle Scholar
  24. 24.
    Vrentzos GE, Papadakis JA, Malliaraki N, Zacharis EA, Mazokopakis E, Margioris A, Ganotakis ES, Kafatos A (2004) Diet, serum homocysteine levels and ischaemic heart disease in a Mediterranean population. Br J Nutr 91:1013–1019CrossRefPubMedGoogle Scholar
  25. 25.
    Ford ES, Smith SJ, Stroup DF, Steinberg KK, Mueller PW, Thacker SB (2002) Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case–control studies and nested case–control studies. Int J Epidemiol 31:59–70. doi: 10.1093/ije/31.1.59 CrossRefPubMedGoogle Scholar
  26. 26.
    Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D’Agostino RB, Wilson PW, Wolf PA (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med 346:476–483. doi: 10.1056/NEJMoa011613 CrossRefPubMedGoogle Scholar
  27. 27.
    McLean RR, Jacques PF, Selhub J, Tucker KL, Samelson EJ, Broe KE, Hannan MT, Cupples LA, Kiel DP (2004) Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med 350:2042–2049. doi: 10.1056/NEJMoa032739 CrossRefPubMedGoogle Scholar
  28. 28.
    Hague WM (2003) Homocysteine and pregnancy. Best Pract Res Clin Obstet Gynaecol 17:459–469. doi: 10.1016/S1521-6934(03)00009-9 CrossRefPubMedGoogle Scholar
  29. 29.
    Russo GT, Di Benedetto A, Alessi E et al (2006) Mild hyperhomocysteinemia and the common C677T polymorphism of methylene tetrahydrofolate reductase gene are not associated with the metabolic syndrome in Type 2 diabetes. J Endocrinol Invest 29:201–207PubMedGoogle Scholar
  30. 30.
    Di Renzo L, Bigioni M, Del Gobbo V et al (2007) Interleukin-1 (IL-1) receptor antagonist gene polymorphism in normal weight obese syndrome: relationship to body composition and IL-1 alpha and beta plasma levels. Pharmacol Res 55:131–138. doi: 10.1016/j.phrs.2006.11.002 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Javad Tavakkoly Bazzaz
    • 1
  • Mahnaz Shojapoor
    • 2
  • Habibollah Nazem
    • 2
  • Parvin Amiri
    • 1
  • Hossein Fakhrzadeh
    • 1
  • Ramin Heshmat
    • 1
  • Maryam Parvizi
    • 1
  • Shirin Hasani Ranjbar
    • 1
  • Mahsa M. Amoli
    • 1
    • 3
  1. 1.Endocrinology and Metabolism Research CentreTehran University of Medical SciencesTehranIran
  2. 2.Department of SciencePayamnoor UniversityTehranIran
  3. 3.EMRC, Dr Shariati HospitalTehranIran

Personalised recommendations