MTHFR C677T and A1298C Gene Polymorphisms and Ischemic Heart Disease (IHD) in a Sri Lankan Population – A Preliminary Study

Rasika Perera, Lal Gotabhaya Chandrasena, Jegarajah Indrakuamar, Hemantha Peiris

Abstract


MTHFR A1298C and C677T SNPs are now recognized as important genetic mutations which would give rise to hyperhomocysteinemia. In this study we analyzed the prevalence of these two SNPs in 79 IHD patients awaiting coronary artery bypass grafting and 79 healthy subjects. MHFR polymorphisms were analyzed using polymerase chain reaction followed by restriction fragment analysis.

Prevalence rates for MTHFR C677T polymorphism were 72.8%, 24.7% and 2.5% for CC, CT and TT genotypes respectively for the whole study population with 677CC genotype being the predominant genotype among both the IHD patients and the controls. The 677TT genotype was detected only among the IHD patients. There was no significant difference in MTHFR 677 genotype variations between IHD patients and the control group. Prevalence rates for the MTHFR A1298C polymorphism were 50%, 37.3% and 12.7% for the AA, AC and CC genotypes respectively for the whole study population with 1298AA genotype being the predominant genotype among controls and 1298AC the predominant genotype among IHD patients. There was a significant difference (p < 0.01) between IHD patients and controls when the MTHFR 1298 genotype variations were compared.

Allele frequencies for the mutant T allele for C677T mutation at 0.149 is the highest reported from Sri Lanka. The frequency of the C for the A1298C mutation was 0.313.

Results of this study indicate that MTHFR A1298C SNP is more prevalent in Sri Lankans when compared to C677T SNP and that the mutant forms of  the MTHFR A1298C SNP are associated with ischemic heart disease.

Keywords:  Methylene tetrahydrofolate reductase, Single Nucleotide polymorphisms, Ischemic heart disease.


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References


Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA. 1995;4:74:1049-57.

Selhub J, Jacques PF, Bostom AG, D'Agostino RB, Wilson PW, Belanger AJ, O'Leary DH, Wolf PA, Schaefer EJ, Rosenberg IH. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995;332:286-91.

Den Heijer M, Koster T, Blom HJ, Bos GM, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med. 1996;334:759-62.

McCully KS. Homocysteine and the pathogenesis of atherosclerosis. Expert Rev Clin Pharmacol. 2015;8:211-219.

Refsum, MD H, Ueland, MD PM, Nygård, MD O, Vollset, MD, Dr. PH SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62.

Goyette P, Christensen B, Rosenblatt DS, Rozen R. Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR. Am J Hum Genet. 1996;59:1268-75.

Goyette P, Frosst P, Rosenblatt DS, Rozen R. Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency. Am J Hum Genet. 1995;56:1052-1059.

Freitas AI, Mendonça I, Guerra G, Brión M, Reis RP, Carracedo A, Brehm A. Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal). Thromb Res. 2008;122:648-56.

Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, Van den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995:10:111-113.

Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mo. Genet Metab. 1998;64:169-72.

van der Put NM, Gabreëls F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, van den Heuvel LP, Blom HJ. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?. Am J Hum Genet. 1998 May 31;62(5):1044-51.

Isotalo PA, Donnelly JG. Prevalence of methylenetetrahydrofolate reductase mutations in patients with venous thrombosis. Mol Diagn. 2000;5:59-66.

Friso S, Jacques PF, Wilson PW, Rosenberg IH, Selhub J. Low circulating vitamin B6 is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation. 2001;103:2788-91.

Hanson NQ, Aras Ö, Yang F, Tsai MY. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem. 2001;47:661-6.

Sabbagh AS, Mahfoud Z, Taher A, Zaatari G, Daher R, Mahfouz RA. High prevalence of MTHFR gene A1298C polymorphism in Lebanon. Genet Test. 2008;12:75-80.

Mendis S, Athauda SB, Kenji T. Association between hyperhomocysteinemia and ischemic heart disease in Sri Lankans. Intl J Cardiol. 1997;62:221-5.

Mendis S, Ranatunga P, Jayatilake M, Wanninayake S, Wickremasinghe R. Hyperhomocysteinaemia in Sri Lankan patients with coronary artery disease. Ceylon Med J. 2011;47:89-92.

Alagratnam D, Wierzbicki AS, Swaminathan R, Turner C, Wickramasinghe SN. Serum homocysteine, folate and thermolabile variant of MTHFR in healthy Sri Lankans living in London. Atherosclerosis. 2000:149:221-2.

Schneider JA, Rees DC, Liu YT, Clegg JB. Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. Am J Hum Genet. 1998;62:1258- 60.

Dissanayake VHW. Inherited factors in pre-eclampsia: Molecular genetic and epidemiological studies in a Sri Lankan population. Dissertation.

van der Put NM, Eskes TK, Blom HJ. Is the common 677C--> T mutation in the methylenetetrahydrofolate reductase gene a risk factor for neural tube defects? A meta-analysis. QJM. 1997;90:111-5.

Papapetrou C, Lynch SA, Burn J, Edwards YH. Methylenetetrahydrofolate reductase and neural tube defects. Lancet. 1996;348:58.

Sohda S, Arinami T, Hamada H, Yamada N, Hamaguchi H, Kubo T. Methylenetetrahydrofolate reductase polymorphism and pre-eclampsia. J Med Genet 1997;34:525-6.

Devi AR, Govindaiah V, Ramakrishna G, Naushad SM. Prevalence of methylene tetrahydrofolate reductase polymorphism in South Indian population. Current Science. 2004;86:440-43.

Angeline T, Jeyaraj N, Granito S, Tsongalis GJ. Prevalence of MTHFR gene polymorphisms (C677T and A1298C) among Tamilians. Exp Mol Pathol 2004;77:85-8.

Kumar J, Das SK, Sharma P, Karthikeyan G, Ramakrishnan L, Sengupta S. Homocysteine levels are associated with MTHFR A1298C polymorphism in Indian population. J Hum Genet. 2005;50:655-63.

Markan S, Sachdeva M, Sehrawat BS, Kumari S, Jain S, Khullar M. MTHFR 677 CT/MTHFR 1298 CC genotypes are associated with increased risk of hypertension in Indians. Mol Cell Biol. 2007;302:125-31.

Brattström L, Wilcken DE, Öhrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease the result of a meta-analysis. Circulation. 1998;98:2520-6.

Guttormsen AB, Ueland PM, Nesthus I, Nygård O, Schneede J, Vollset SE, Refsum H. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or= 40 micromol/liter). The Hordaland Homocysteine Study. J Clin Invest. 1996;98:2174-83.

Mehlig K, Leander K, De Faire U, Nyberg F, Berg C, Rosengren A, Björck L, Zetterberg H, Blennow K, Tognon G, Torén K. The association between plasma homocysteine and coronary heart disease is modified by the MTHFR 677C> T polymorphism. Heart. 2013;99: 1761–65.




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