Molecular and Cellular Biochemistry

, Volume 302, Issue 1–2, pp 125–131 | Cite as

MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians

  • Suchita Markan
  • Meenakshi Sachdeva
  • Badan Singh Sehrawat
  • Savita Kumari
  • Sanjay Jain
  • Madhu Khullar
Article

Abstract

The goals of our present study were to measure plasma homocysteine levels and determine their association with methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (C677T and A1298C) in essential hypertensive subjects. Plasma total homocysteine and folic acid levels were measured in essential hypertensive patients (n = 153) before and after oral supplementation with either 5 mg folic acid tablet/day or 5 mg placebo/day for 4 weeks and compared with age and sex matched normotensive controls (n = 133). MTHFR gene polymorphisms (C677T and A1298C) were studied by restriction fragment length polymorphism and correlated with plasma homocysteine levels. Homocysteine levels were significantly higher in hypertensive patients as compared to controls and showed a negative correlation with plasma folate levels. Folic acid supplementation (5 mg/day) for 4 weeks resulted in a significant decrease in plasma homocysteine concentrations in these patients. Patients carrying MTHFR 677T allele (OR = 1.90; 95%CI: 1.14–3.19) or MTHFR 1298C (OR = 2.6, 95%CI: 1.55–4.40) allele were at increased risk of hypertension. The frequency of co-occurrence of MTHFR 677 CT/1298 CC genotypes was significantly higher in the patients compared to controls (P < 0.05) and was associated with increased risk of hypertension (OR = 3.54, 95%CI: 0.37–4.30). Subjects with MTHFR 1298 CC genotype had significantly higher homocysteine levels compared to those with MTHFR 1298 AA genotype (P < 0.05). Our results indicate that MTHFR 677T and 1298C alleles and co-occurrence of MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension and MTHFR 1298 CC genotype is associated with higher homocysteine levels in our subjects.

Keywords

Methylenetetrahydrofolate reductase (MTHFR) Homocysteine Folate MTHFR C677T MTHFR A1298C 

References

  1. 1.
    Lim U, Cassano PA (2002) Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol 156:1105–1113PubMedCrossRefGoogle Scholar
  2. 2.
    Pierdomenico SD, Bucci A, Lapenna D, Lattanzio FM, Talone L, Cuccurullo F, Mezzetti A (2003) Circulating homocysteine levels in sustained and white coat hypertension. J Hum Hypertens 17:165–170PubMedCrossRefGoogle Scholar
  3. 3.
    Rolland PH, Friggi A, Barlatier A, Piquet P, Latrille V, Faye MM, Guillou J, Charpiot P, Bodard H, Ghiringhelli O, Calaf R, Luccioni R, Garçon D (1995) Hyperhomocysteinemia-induced vascular damage in the mini pig: captopril-hydrochlorothiazide combination prevents elastic alterations. Circulation 91:1161–1174PubMedGoogle Scholar
  4. 4.
    Curgunlu A, Karter Y, Uzun H, Aydin S, Erturk N, Vehid S, Simsek G, Kutlu A, Ozturk E, Erdine S (2005) Hyperhomocysteinemia: an additional risk factor in white coat hypertension. Int Heart J 46:245–254PubMedCrossRefGoogle Scholar
  5. 5.
    Jain S, Ram H, Kumari S, Khullar M (2003) Plasma homocysteine levels in Indian patients with essential hypertension and their siblings. Ren Fail 25:195–201PubMedCrossRefGoogle Scholar
  6. 6.
    Mangoni AA, Sherwood RA, Swift CG, Jackson SH (2002) Folic acid enhances endothelial function and reduces blood pressure in smokers: a randomized controlled trial. J Intern Med 252:497–503PubMedCrossRefGoogle Scholar
  7. 7.
    van Dijk RA, Rauwerda JA, Steyn M, Twisk JW, Stehouwer CD (2001) Long-term homocysteine-lowering treatment with folic acid plus pyridoxine is associated with decreased blood pressure but not with improved brachial artery endothelium-dependent vasodilation or carotid artery stiffness: a 2-year, randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol 21:2072–2079PubMedGoogle Scholar
  8. 8.
    Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma RRJ, Boers GH, Sheahan RG, Israelsson B, Uiterwaal CS, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht JC, de Valk HW, Sales LAC, Parrot RFM, Tan KS, Higgins I, Garcon D, Andria G (1997) Plasma homocysteine as a risk factor for vascular disease: the European Concerted Action Project. JAMA 277:1775–1781PubMedCrossRefGoogle Scholar
  9. 9.
    Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE, Ueland M, Kvale G (1995) Total plasma homocysteine and cardiovascular risk profile: the Hordaland Homocysteine Study. JAMA 274:1526–1533PubMedCrossRefGoogle Scholar
  10. 10.
    Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J (2001) Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort. Am J Clin Nutr 73:613–621PubMedGoogle Scholar
  11. 11.
    Kahleova R, Palyzova D, Zvara K, Zvarova J, Hrach K, Novakova I, Hyanek J, Bendlova B, Kozich V (2002) Essential hypertension in adolescents: association with insulin resistance and with metabolism of homocysteine and vitamins. J Hypertens 15:857–864CrossRefGoogle Scholar
  12. 12.
    Guldener VC, Nanayakkara PW, Stehouwer CD (2003) Homocysteine and blood pressure. Curr Hypertens Rep 5:26–31PubMedCrossRefGoogle Scholar
  13. 13.
    Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuve LP, Rozen R (1995) A candidate genetic risk factor for vascular disease a common mutation in methyltetrahydrofolate reductase. Nat Genet 10:111–113PubMedCrossRefGoogle Scholar
  14. 14.
    Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methyltetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64:169–172PubMedCrossRefGoogle Scholar
  15. 15.
    Weisberg IS, Jacques PF, Selhub J, Bostom AG, Chen Z, Curtis ER, Eckfeldt JH, Rozen R (2001) The 1298A > C polymorphism in methyltetrahydrofolate reductase (MTHFR): in vitro expression and association with homocysteine. Atherosclerosis 156:409–415PubMedCrossRefGoogle Scholar
  16. 16.
    Heux S, Morin F, Lea RA, Ovcaric M, Tajouri L, Griffiths LR (2004) The methylentetrahydrofolate reductase gene variant (C677T) as a risk factor for essential hypertension in Caucasians. Hypertens Res 27:663–667PubMedCrossRefGoogle Scholar
  17. 17.
    Koupepidou P, Deltas C, Christofides TC, Athanasiou Y, Zouvani I, Pierides A (2005) The MTHFR 677TT and 677CT/1298AC genotypes in Cypriot patients may be predisposing to hypertensive nephrosclerosis and chronic renal failure. Int Angiol 24:287–294PubMedGoogle Scholar
  18. 18.
    Jiang S, Hsu YH, Niu T, Xu X, Xing H, Chen C, Wang X, Zhang Y, Peng S, Xu X (2005) A common haplotype on methylenetetrahydrofolate reductase gene modifies the effect of angiotensin-converting enzyme inhibitor on blood pressure in essential hypertension patients-a family-based association study. Clin Exp Hypertens 27:509–521PubMedCrossRefGoogle Scholar
  19. 19.
    Lahiri DK, Nurnberger JI (1991) A rapid non-enzymatic method for the preparation of high molecular weight DNA from blood for RFLP studies. Nucleic Acids Res 355:523–527Google Scholar
  20. 20.
    Sundstrom J, Sullivan L, D’Agostino RB, Jacques PF, Selhub J, Rosenberg IH, Wilson PW, Levy D, Vasan RS (2003) Plasma homocysteine, hypertension incidence, and blood pressure tracking: the Framingham heart study. Hypertension 42:1100–1105PubMedCrossRefGoogle Scholar
  21. 21.
    Rolland PH, Friggi A, Barlatier A, Piquet P, Latrille V, Faye MM, Guillou J, Charpiot P, Bodard H, Ghiringhelli O, Calaf R, Luccioni R, Garçon D (1995) Hyperhomocysteinemia-induced vascular damage in the minipig: captopril-hydrochlorothiazide combination prevents elastic alterations. Circulation 91:1161–1174PubMedGoogle Scholar
  22. 22.
    Hughes K, Ong CN (2000) Homocysteine, folate, vitamin B12, and cardiovascular risk in Indian, Malay, and Chinese in Singapore. J Epidemiol Community Health 54:31–34PubMedCrossRefGoogle Scholar
  23. 23.
    Misra A, Vikram NK, Pandey RM, Dwivedi M, Ahmad FU, Luthra K, Jain K, Khanna N, Devi JR, Sharma R, Guleria R (2002) Hyperhomocysteinemia and low intakes of folic acid and vitamin B12 in urban North India. Eur J Nutr 41:68–77PubMedCrossRefGoogle Scholar
  24. 24.
    Kostulas K, Crisby M, Huang WX, Lannfelt L, Hagenfeldt L, Eggertsen G, Kostulas V, Hillert J (1998) A methylenetetrahydrofolate reductase gene polymorphism in ischaemic stroke and in carotid artery stenosis. Eur J Clin Invest 28:285–289PubMedCrossRefGoogle Scholar
  25. 25.
    Verhoef P, Kok FJ, Kluijtmans LA, Blom HJ, Refsum H, Ueland PM, Kruyssen DA (1997) The 677C > T mutation in the methylenetetrahydrofolate reductase gene: associations with plasma total homocysteine levels and risk of coronary atherosclerotic disease. Atherosclerosis 132:105–113PubMedCrossRefGoogle Scholar
  26. 26.
    Dedoussis GV, Panagiotakos DB, Chrysohoou C, Pitsavos C, Zampelas A, Choumerianou D, Stefanadis C (2004) Effect of interaction between adherence to a Mediterranean diet and the methylenetetrahydrofolate reductase 677C > T mutation on homocysteine concentrations in healthy adults: the ATTICA Study. Am J Clin Nutr 80:849–854PubMedGoogle Scholar
  27. 27.
    Inamoto N, Katsuya T, Kokubo Y, Mannami T, Asai T, Baba S, Ogata J, Tomoike H, Ogihara T (2003) Association of methylenetetrahydrofolate reductase gene polymorphism with carotid atherosclerosis depending on smoking status in a Japanese general population. Stroke 34:1628–1633PubMedCrossRefGoogle Scholar
  28. 28.
    Benes P, Kankova K, Muzik J, Groch L, Benedik J, Elbl L, Izakovicova-Holla L, Vasku A, Znojil V, Vacha J (2001) Methylenetetrahydrofolate reductase polymorphism, type II diabetes mellitus, coronary artery disease, and essential hypertension in the Czech population. J Mol Genet Metab 73:188–195CrossRefGoogle Scholar
  29. 29.
    Friedman G, Goldschmidt N, Friedlander Y, Ben YA, Selhub J, Babaey S, Mendel M, Kidron M, Bar OH (1999) A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr 129:1656–1661PubMedGoogle Scholar
  30. 30.
    Amero A, Khaled K, Wyngaard CA, Dzimiri N (2003) Prevalence and role of methylenetetrahydrofolate reductase C677T and A1298C polymorphisms in coronary artery disease in Arabs. Arch Pathol Lab Med 127:1349–1352PubMedGoogle Scholar
  31. 31.
    Angeline T, Jeyaraj N, Granito S, Tsongalis GJ (2004) Prevalence of MTHFR gene polymorphisms(C677T and A1298C) among Tamilians. Exp Mol Pathol 77:85–88PubMedCrossRefGoogle Scholar
  32. 32.
    Lievers KJ, Boers GH, Verhoef P, Heijer DM, Kluijtmans LA, Put VNM, Trijbels FJ, Blom HJ (2001) A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk. J Mol Med 79:522–528PubMedCrossRefGoogle Scholar
  33. 33.
    Castro R, Rivera P, Ravasco C, Jacobs HJ, Blom ME, Camilo IT, Alemeida D (2003) 5, 10-Methylenetetrahydrofolate reductase 677C > T and1298A > C mutations are genetic determinants of elevated homocysteine. QJM 96:297–303PubMedCrossRefGoogle Scholar
  34. 34.
    Williams C, Kingwell BA, Burke K, McPherson J, Dart AM (2005) Folic acid supplementation for 3 wk reduces pulse pressure and large artery stiffness independent of MTHFR genotype. Am J Clin Nutr 82:26–31PubMedGoogle Scholar
  35. 35.
    Ogino S, Wilson RB (2003) Genotype and haplotype distributions of MTHFR677C > T and 1298A > C single nucleotide polymorphisms: a meta-analysis. J Hum Genet 48:1–7PubMedCrossRefGoogle Scholar
  36. 36.
    Hernandez DS, Wu XF, Hayes C, Werler MM, Ashok TD, Badovinac R, Kelsey KT, Mitchell AA (2005) Methylenetetrahydrofolate reductase polymorphisms and the risk of gestational hypertension. Epidemiology 16:628–634CrossRefGoogle Scholar
  37. 37.
    Kumar J, Das SK, Sharma P, Karthikeyan G, Ramakrishnan L, Sengupta S (2005) Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population. J Hum Genet 50:655–663PubMedCrossRefGoogle Scholar
  38. 38.
    Strauss E, Gluszek J, Pawlak AL (2005) Age and hypertension related changes in genotypes of MTHFR C677T, A1298C and PON1 −108C > T SNPs in men with coronary artery disease (CAD). J Physiol Pharmacol 56:65–75PubMedGoogle Scholar
  39. 39.
    Botto L, Yang Q (2000) 5, 10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 151:862–877PubMedGoogle Scholar
  40. 40.
    Volcik KA, Blanton SH, Northrup H (2001) Examinations of methylenetetrahydrofolate reductase C677T and A1298C mutations and in utero viability. Am J Hum Genet 69:1150–1153PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Suchita Markan
    • 1
  • Meenakshi Sachdeva
    • 1
  • Badan Singh Sehrawat
    • 1
  • Savita Kumari
    • 2
  • Sanjay Jain
    • 2
  • Madhu Khullar
    • 1
  1. 1.Department of Experimental Medicine and BiotechnologyPost Graduate Institute of Medical Education and ResearchChandigarhIndia
  2. 2.Department of Internal MedicinePost Graduate Institute of Medical Education and ResearchChandigarhIndia

Personalised recommendations