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

Molecular and Cellular Biochemistry volume 302, pages 125–131 (2007)Cite this 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.

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References

  1. Lim U, Cassano PA (2002) Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol 156:1105–1113

    PubMed  Article  Google Scholar 

  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 17:165–170

    PubMed  Article  CAS  Google Scholar 

  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 91:1161–1174

    PubMed  CAS  Google Scholar 

  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 46:245–254

    PubMed  Article  CAS  Google Scholar 

  5. Jain S, Ram H, Kumari S, Khullar M (2003) Plasma homocysteine levels in Indian patients with essential hypertension and their siblings. Ren Fail 25:195–201

    PubMed  Article  CAS  Google Scholar 

  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 252:497–503

    PubMed  Article  CAS  Google Scholar 

  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 21:2072–2079

    PubMed  Google Scholar 

  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 277:1775–1781

    PubMed  Article  CAS  Google Scholar 

  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 274:1526–1533

    PubMed  Article  CAS  Google Scholar 

  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 73:613–621

    PubMed  CAS  Google Scholar 

  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 15:857–864

    Article  CAS  Google Scholar 

  12. Guldener VC, Nanayakkara PW, Stehouwer CD (2003) Homocysteine and blood pressure. Curr Hypertens Rep 5:26–31

    PubMed  Article  Google Scholar 

  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 10:111–113

    PubMed  Article  CAS  Google Scholar 

  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 64:169–172

    PubMed  Article  CAS  Google Scholar 

  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 156:409–415

    PubMed  Article  CAS  Google Scholar 

  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 27:663–667

    PubMed  Article  CAS  Google Scholar 

  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 24:287–294

    PubMed  CAS  Google Scholar 

  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 27:509–521

    PubMed  Article  CAS  Google Scholar 

  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 355:523–527

    Google Scholar 

  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 42:1100–1105

    PubMed  Article  Google Scholar 

  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 91:1161–1174

    PubMed  CAS  Google Scholar 

  22. Hughes K, Ong CN (2000) Homocysteine, folate, vitamin B12, and cardiovascular risk in Indian, Malay, and Chinese in Singapore. J Epidemiol Community Health 54:31–34

    PubMed  Article  CAS  Google Scholar 

  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 41:68–77

    PubMed  Article  CAS  Google Scholar 

  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 28:285–289

    PubMed  Article  CAS  Google Scholar 

  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 132:105–113

    PubMed  Article  CAS  Google Scholar 

  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 80:849–854

    PubMed  CAS  Google Scholar 

  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 34:1628–1633

    PubMed  Article  CAS  Google Scholar 

  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 73:188–195

    Article  CAS  Google Scholar 

  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 129:1656–1661

    PubMed  CAS  Google Scholar 

  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 127:1349–1352

    PubMed  Google Scholar 

  31. Angeline T, Jeyaraj N, Granito S, Tsongalis GJ (2004) Prevalence of MTHFR gene polymorphisms(C677T and A1298C) among Tamilians. Exp Mol Pathol 77:85–88

    PubMed  Article  CAS  Google Scholar 

  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 79:522–528

    PubMed  Article  CAS  Google Scholar 

  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 96:297–303

    PubMed  Article  CAS  Google Scholar 

  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 82:26–31

    PubMed  CAS  Google Scholar 

  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 48:1–7

    PubMed  Article  CAS  Google Scholar 

  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 16:628–634

    Article  Google Scholar 

  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 50:655–663

    PubMed  Article  CAS  Google Scholar 

  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 56:65–75

    PubMed  Google Scholar 

  39. Botto L, Yang Q (2000) 5, 10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol 151:862–877

    PubMed  CAS  Google Scholar 

  40. Volcik KA, Blanton SH, Northrup H (2001) Examinations of methylenetetrahydrofolate reductase C677T and A1298C mutations and in utero viability. Am J Hum Genet 69:1150–1153

    PubMed  Article  CAS  Google Scholar 

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Acknowledgment

Supported by research funding from Indian Council of Medical Research, New Delhi, India.

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Affiliations

  1. Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research, Laboratory no. 2033, Research block B, Chandigarh, 160012, India

    Suchita Markan, Meenakshi Sachdeva, Badan Singh Sehrawat & Madhu Khullar

  2. Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India

    Savita Kumari & Sanjay Jain

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  1. Suchita Markan
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  2. Meenakshi Sachdeva
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Correspondence to Madhu Khullar.

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Markan, S., Sachdeva, M., Sehrawat, B.S. et al. MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians. Mol Cell Biochem 302, 125–131 (2007). https://doi.org/10.1007/s11010-007-9434-5

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  • DOI: https://doi.org/10.1007/s11010-007-9434-5

Keywords

  • Methylenetetrahydrofolate reductase (MTHFR)
  • Homocysteine
  • Folate
  • MTHFR C677T
  • MTHFR A1298C