Association of polymorphism in the thermolabile 5, 10-methylene tetrahydrofolate reductase gene and hyperhomocysteinemia with coronary artery disease
- 157 Downloads
Objective To determine the incidence of methylene tetrahydrofolate reductase (MTHFR) gene 677C→T polymorphism and plasma homocysteine (Hcy) levels in a group of subjects who underwent coronary angiography, in an attempt to establish a correlation between these parameters and the severity of coronary artery disease (CAD) and to investigate the correlation between hyperhomocysteinemia (HHcy) and the presence of 677C→T polymorphism. Background Elevated plasma Hcy level is an independent risk factor for CAD. A common mutation (677C→T) in the gene coding for MTHFR has been reported to reduce the enzymatic activity and is associated with elevated levels of Hcy, especially in subjects with low folate intake. Methods The study group comprised of 84 patients with CAD and 100 age-and-sex matched controls who had no history or clinical evidence of CAD and/or MI. DNA was extracted from peripheral blood and genotypes were determined by polymerase chain reaction, restriction mapping with Hinf1, and gel electrophoresis. Conventional risk factors for CAD were prospectively documented. Results Allele and genotype frequencies in cases and control subjects were compatible with Hardy–Weinberg equilibrium. The frequencies of TT, CT, and CC genotypes among CAD patients were 4.8, 27.4, and 67.8% and in controls were 1.0, 19.0, and 80%. Hcy levels were higher in patients with triple-vessel disease compared to single and double vessel disease (P = 0.002). Multivariate analyses identified HHcy, diabetes mellitus, and hypertension as the independent predictors of CAD. Conclusions HHcy appears to have a graded effect on the risk of CAD as well as the severity and extent of coronary atherosclerosis. Our findings support that homozygous genotype of MTHFR is a genetic risk factor for CAD. A further study with larger sample size including assessment of vitamin status is needed to better clarify the relationship between MTHFR genotypes and CAD.
KeywordsHyperhomocysteinemia Methylene tetrahydrofolate reductase Coronary artery disease
This study was supported by the grants from Indian Council of Medical Research, Ministry of Health, Government of India.
- 5.Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJH, den Heijer M, Kluijtmans LAJ, van den Heuvel LP, Rozen R (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylene tetrahydrofolate reductase. Nat Genet 10:111–113PubMedCrossRefGoogle Scholar
- 7.Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y (1997) Genetic polymorphism of 5,10-methylene tetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation 95:2032–2036PubMedGoogle Scholar
- 8.Kluijtmans LAJ, van den Heuvel LP, Boers GHJ, Frosst P, Stevens EMB, van Oost BA, den Heijer M, Trijbels FJM, Rozen R, Blom HJ (1996) Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylene tetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease. Am J Hum Genet 58:35–41PubMedGoogle Scholar
- 9.Meleady R, Ueland PM, Blom B, Whitehead AS, Refsum H, Daly LE, Vollset SE, Donohue C, Giesendorf B, Graham IM, Ulvik A, Zhang Y, Monsen ALB (2003) Thermolabile methylene tetrahydrofolate reductase, homocysteine, and cardiovascular disease risk: The European Concerted Action Project. Am J Clin Nutr 77:63–70PubMedGoogle Scholar
- 12.Gardemann A, Weidemann H, Philipp M, Katz N, Tillmanns H, Hehrlein FW, Haberbosch W (1999) The TT genotype of the methylene tetrahydrofolate reductase C677T gene polymorphism is associated with the extent of coronary atherosclerosis in patients at high risk for coronary artery disease. Eur Heart J 20:584–592PubMedCrossRefGoogle Scholar
- 13.Laraqui A, Allami A, Carrié A, Raisonnier A, Coiffard AS, Benkouka F, Bendriss A, Benjouad A, Bennouar N, El Kadiri N, Benomar A, Fellat S, Benomar M (2007) Relation between plasma homocysteine, gene polymorphisms of homocysteine metabolism-related enzymes, and angiographically proven coronary artery disease. Eur J Intern Med 18:474–483PubMedCrossRefGoogle Scholar
- 17.Nair KG, Nair SR, Ashavaid TF, Dalal JJ, Eghlim FF (2002) Methylene tetrahydrofolate reductase gene mutation and hyperhomocysteinemia as a risk factor for coronary heart disease in the Indian population. J Assoc Physicians India 50:S9–S15Google Scholar
- 20.Karthikeyan G, Prabhakaran D, Reddy KS (2002) Plasma homocysteine levels and cardiovascular risk in Indians. J Assoc Physicians India 50:S24–S28Google Scholar
- 28.Vasisht S, Gulati R, Narang R, Srivastava N, Srivastava LM, Manchanda SC, Agarwal DP (2002) Polymorphism (C677T) in the 5,10- methylene tetrahydrofolate reductase gene: a preliminary study on North Indian men. Indian J Clin Biochem 17:99–107Google Scholar