Thermolabile Methylenetetrahydrofolate Reductase  C677T Polymorphism and Homocysteine Are Risk Factors  for Coronary Artery Disease in Moroccan Population

Bennouar, Nawal; Allami, Abdellatif; Azeddoug, Houssine; Bendris, Abdenbi; Laraqui, Abdelilah; El Jaffali, Amal; El Kadiri, Nizar; Benzidia, Rachid; Benomar, Anwar; Fellat, Seddik; Benomar, Mohamed

doi:https://doi.org/10.1155/2007/80687

BioMed Research International

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Research Article | Open Access

Volume 2007 | Article ID 080687 | https://doi.org/10.1155/2007/80687

Thermolabile Methylenetetrahydrofolate Reductase C677T Polymorphism and Homocysteine Are Risk Factors for Coronary Artery Disease in Moroccan Population

Nawal Bennouar,^1,2Abdellatif Allami,^1,3Houssine Azeddoug,²Abdenbi Bendris,³Abdelilah Laraqui,¹Amal El Jaffali,¹Nizar El Kadiri,¹Rachid Benzidia,⁴Anwar Benomar,¹Seddik Fellat,¹and Mohamed Benomar⁴

Academic Editor: Mohamed Boutjdir

Received21 Sept 2006

Revised20 Dec 2006

Accepted09 Jan 2007

Published07 Mar 2007

Abstract

Increased plasma total homocysteine (tHcy) levels have been shown to be a risk factor for coronary artery disease (CAD). The common methylenetetrahydrofolate reductase C677T (MTHFR C677T) polymorphism has been reported to be a strong predictor of mild hyperhomocysteinaemia (HHcy). We assessed whether this mutation was associated with increased risk of CAD and plasma levels of tHcy. We also evaluated interactions between this polymorphism, mild elevated tHcy levels and conventional risk factors of CAD. Method. Using PCR-RFLP analysis, we studied the frequency of the C677T genotypes and its effect on CAD and on tHcy concentrations in 400 subjects without and with CAD angiographically confirmed. There were 210 subjects with CAD and 190 subjects without CAD. Results. The frequencies of the C677T genotypes were 53% (59.5% in controls versus 48.1% in cases), 34.8% (32.1 in controls versus 37.1 in cases), and 11.8% (8.4% in controls versus 14.8% in cases), respectively, for 677CC, 677CT, and 677TT. The genotype frequencies were significantly different between case and control groups (P<.05). The 677T allele enhances the risk of CAD associated to HHcy (P<.01). In multivariate analysis models, MTHFR C677T polymorphism effect on CAD was masked by other risk factors. HHcy was only and independently influenced by MTHFR polymorphism and smoking habits, and it is a strong predictor of CAD independently of conventional risk factors. Conclusion. Our data suggest that HHcy is strongly and independently associated to CAD risk increase; and MTHFR C677T polymorphism and smoking habits were the main predictors of tHcy levels. The CAD risk increase is mainly associated with mild HHcy in 677TT, whereas in 677CT and 677CC it is mainly associated with the conventional risk factors.

References

A. J. Lusis, R. Mar, and P. Pajukanta, “Genetics of atherosclerosis,” Annual Review of Genomics and Human Genetics, vol. 5, pp. 189–218, 2004.
View at: Publisher Site | Google Scholar
R. A. Hegele and R. L. Pollex, “Genetic and physiological insights into the metabolic syndrome,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 289, no. 3, pp. R663–R669, 2005.
View at: Publisher Site | Google Scholar
J. Geisel, I. Zimbelmann, H. Schorr et al., “Genetic defects as important factors for moderate hyperhomocysteinemia,” Clinical Chemistry and Laboratory Medicine, vol. 39, no. 8, pp. 698–704, 2001.
View at: Publisher Site | Google Scholar
C. J. Boushey, S. A. A. Beresford, G. S. Omenn, and A. G. Motulsky, “A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes,” Journal of the American Medical Association, vol. 274, no. 13, pp. 1049–1057, 1995.
View at: Publisher Site | Google Scholar
N. M. J. van der Put, R. P. M. Steegers-Theunissen, P. Frosst et al., “Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida,” The Lancet, vol. 346, no. 8982, pp. 1070–1071, 1995.
View at: Publisher Site | Google Scholar
S.-S. Kang and P. W. K. Wong, “Genetic and nongenetic factors for moderate hyperhomocyst(e)inemia,” Atherosclerosis, vol. 119, no. 2, pp. 135–138, 1996.
View at: Publisher Site | Google Scholar
S.-S. Kang, P. W. K. Wong, A. Susmano, J. Sora, M. Norusis, and N. Ruggie, “Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease,” American Journal of Human Genetics, vol. 48, no. 3, pp. 536–545, 1991.
View at: Google Scholar
S.-S. Kang, E. L. Passen, N. Ruggie, P. W. K. Wong, and H. Sora, “Thermolabile defect of methylenetetrahydrofolate reductase in coronary artery disease,” Circulation, vol. 88, no. 4 part 1, pp. 1463–1469, 1993.
View at: Google Scholar
A. M. T. Engbersen, D. G. Franken, G. H. J. Boers, E. M. B. Stevens, F. J. M. Trijbels, and H. J. Blom, “Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia,” American Journal of Human Genetics, vol. 56, no. 1, pp. 142–150, 1995.
View at: Google Scholar
P. F. Jacques, A. G. Bostom, R. R. Williams et al., “Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations,” Circulation, vol. 93, no. 1, pp. 7–9, 1996.
View at: Google Scholar
P. Frosst, H. J. Blom, R. Milos et al., “A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase,” Nature Genetics, vol. 10, no. 1, pp. 111–113, 1995.
View at: Publisher Site | Google Scholar
L. A. J. Kluijtmans, L. P. W. J. van den Heuvel, G. H. J. Boers et al., “Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetetrahydrofolate reductase gene is a genetic risk factor for cardiovascular disease,” American Journal of Human Genetics, vol. 58, no. 1, pp. 35–41, 1996.
View at: Google Scholar
F. Frantzen, A. L. Faaren, I. Alfheim, and A. K. Nordhei, “Enzyme conversion immunoassay for determining total homocysteine in plasma or serum,” Clinical Chemistry, vol. 44, no. 2, pp. 311–316, 1998.
View at: Google Scholar
A. Laraqui, N. Bennouar, F. Meggouh et al., “Homocysteine, lipoprotein (a): risk factors for coronary heart disease,” Annales de Biologie Clinique, vol. 60, no. 5, pp. 549–557, 2002.
View at: Google Scholar
W. G. Christen, U. A. Ajani, R. J. Glynn, and C. H. Hennekens, “Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual?” Archives of Internal Medicine, vol. 160, no. 4, pp. 422–434, 2000.
View at: Publisher Site | Google Scholar
K. S. McCully, “Homocysteine and vascular disease,” Nature Medicine, vol. 2, no. 4, pp. 386–389, 1996.
View at: Publisher Site | Google Scholar
J. Selhub and A. D'Angelo, “Hyperhomocysteinemia and thrombosis: acquired conditions,” Thrombosis and Haemostasis, vol. 78, no. 1, pp. 527–531, 1997.
View at: Google Scholar
M. J. Stampfer, M. R. Malinow, W. C. Willett et al., “A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians,” Journal of the American Medical Association, vol. 268, no. 7, pp. 877–881, 1992.
View at: Publisher Site | Google Scholar
E. Arnesen, H. Refsum, K. H. Bonaa, P. M. Ueland, O. H. Forde, and J. E. Nordrehaug, “Serum total homocysteine and coronary heart disease,” International Journal of Epidemiology, vol. 24, no. 4, pp. 704–709, 1995.
View at: Publisher Site | Google Scholar
R. W. Evans, B. J. Shaten, J. D. Hempel, J. A. Cutler, and L. H. Kuller, “Homocyst(e)ine and risk of cardiovascular disease in the multiple risk factor intervention trial,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 17, no. 10, pp. 1947–1953, 1997.
View at: Google Scholar
A. R. Folsom, F. J. Nieto, P. G. McGovern et al., “Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the atherosclerosis risk in communities (ARIC) study,” Circulation, vol. 98, no. 3, pp. 204–210, 1998.
View at: Google Scholar
D. S. Wald, M. Law, and J. K. Morris, “Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis,” British Medical Journal, vol. 325, no. 7374, pp. 1202–1206, 2002.
View at: Publisher Site | Google Scholar
D. E. Zylberstein, C. Bengtsson, C. Björkelund et al., “Serum homocysteine in relation to mortality and morbidity from coronary heart disease: a 24-year follow-up of the population study of women in gothenburg,” Circulation, vol. 109, no. 5, pp. 601–606, 2004.
View at: Publisher Site | Google Scholar
M. A. Tazi, S. Abir-Khalil, N. Chaouki et al., “Prevalence of the main cardiovascular risk factors in Morocco: results of a national survey, 2000,” Journal of Hypertension, vol. 21, no. 5, pp. 897–903, 2003.
View at: Publisher Site | Google Scholar
L. M. Graham, L. E. Daly, H. M. Refsum et al., “Plasma homocysteine as a risk factor for vascular disease: The European Concerted Action Project,” Journal of the American Medical Association, vol. 277, no. 22, pp. 1775–1781, 1997.
View at: Publisher Site | Google Scholar
S. L. Tokgözoglu, M. Alikasifoglu, I. Ünsal et al., “Methylene tetrahydrofolate reductase genotype and the risk and extent of coronary artery disease in a population with low plasma folate,” Heart, vol. 81, no. 5, pp. 518–522, 1999.
View at: Google Scholar
O. Nygard, S. E. Vollset, H. Refsum et al., “Total plasma homocysteine and cardiovascular risk profile: the Hordaland homocysteine study,” Journal of the American Medical Association, vol. 274, no. 19, pp. 1526–1533, 1995.
View at: Publisher Site | Google Scholar
C. E. Bartecchi, T. D. MacKenzie, and R. W. Schrier, “The human costs of tobacco use (1),” New England Journal of Medicine, vol. 330, no. 13, pp. 907–912, 1994.
View at: Google Scholar
T. D. MacKenzie, C. E. Bartecchi, and R. W. Schrier, “The human costs of tobacco use (2),” New England Journal of Medicine, vol. 330, no. 14, pp. 975–980, 1994.
View at: Publisher Site | Google Scholar
R. H. Fryer, B. D. Wilson, D. B. Gubler, L. A. Fitzgerald, and G. M. Rodgers, “Homocysteine, a risk factor for premature vascular disease and thrombosis, induces tissue factor activity in endothelial cells,” Arteriosclerosis and Thrombosis, vol. 13, no. 9, pp. 1327–1333, 1993.
View at: Google Scholar
L. A. Harker, R. Ross, S. J. Slichter, and C. R. Scott, “Homocystine induced arteriosclerosis. The role of endothelial cell injury and platelet response in its genesis,” Journal of Clinical Investigation, vol. 58, no. 3, pp. 731–741, 1976.
View at: Google Scholar
F. Nappo, N. de Rosa, R. Marfella et al., “Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins,” Journal of the American Medical Association, vol. 281, no. 22, pp. 2113–2118, 1999.
View at: Publisher Site | Google Scholar
S. C. de Jong, C. D. A. Stehouwer, M. van den Berg, U. M. Vischer, J. A. Rauwerda, and J. J. Emeis, “Endothelial marker proteins in hyperhomocysteinemia,” Thrombosis and Haemostasis, vol. 78, no. 5, pp. 1332–1337, 1997.
View at: Google Scholar
G. R. Upchurch Jr., G. N. Welch, A. J. Fabian, A. Pigazzi, J. F. Keaney Jr., and J. Loscalzo, “Stimulation of endothelial nitric oxide production by homocyst(e)ine,” Atherosclerosis, vol. 132, no. 2, pp. 177–185, 1997.
View at: Publisher Site | Google Scholar
K. S. Woo, P. Chook, Y. I. Lolin, J. E. Sanderson, C. Metreweli, and D. S. Celermajer, “Folic acid improves arterial endothelial function in adults with hyperhomocystinemia,” Journal of the American College of Cardiology, vol. 34, no. 7, pp. 2002–2006, 1999.
View at: Publisher Site | Google Scholar
C. Legnani, G. Palareti, F. Grauso et al., “Hyperhomocyst(e)inemia and a common methylenetetrahydrofolate reductase mutation ( ${Ala}^{223}$ Val MTHFR) in patients with inherited thrombophilic coagulation defects,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 17, no. 11, pp. 2924–2929, 1997.
View at: Google Scholar
P. M. Ridker, C. H. Hennekens, J. Selhub, J. P. Miletich, M. R. Malinow, and M. J. Stampfer, “Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism,” Circulation, vol. 95, no. 7, pp. 1777–1782, 1997.
View at: Google Scholar
J. G. Ray, “Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease,” Archives of Internal Medicine, vol. 158, no. 19, pp. 2101–2106, 1998.
View at: Publisher Site | Google Scholar
L. Brattström, D. E. L. Wilcken, J. Öhrvik, and L. Brudin, “Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta- analysis,” Circulation, vol. 98, no. 23, pp. 2520–2526, 1998.
View at: Google Scholar
H. Morita, J.-I. Taguchi, H. Kurihara et al., “Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease,” Circulation, vol. 95, no. 8, pp. 2032–2036, 1997.
View at: Google Scholar
J. L. Anderson, G. J. King, M. J. Thomson et al., “A mutation in the methylenetetrahydrofolate reductase gene is not associated with increased risk for coronary artery disease or myocardial infarction,” Journal of the American College of Cardiology, vol. 30, no. 5, pp. 1206–1211, 1997.
View at: Publisher Site | Google Scholar
J. Ma, M. J. Stampfer, C. H. Hennekens et al., “Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians,” Circulation, vol. 94, no. 10, pp. 2410–2416, 1996.
View at: Google Scholar
E. S. Brilakis, P. B. Berger, K. V. Ballman, and R. Rozen, “Methylenetetrahydrofolate reductase (MTHFR) 677C $\to$ T and methionine synthase reductase (MTRR) 66A $\to$ G polymorphisms: association with serum homocysteine and angiographic coronary artery disease in the era of flour products fortified with folic acid,” Atherosclerosis, vol. 168, no. 2, pp. 315–322, 2003.
View at: Publisher Site | Google Scholar

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Copyright © 2007 Nawal Bennouar et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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