Association of MTRR A66G polymorphism (but not of MTHFR C677T and A1298C, MTR A2756G, TCN C776G) with homocysteine and coronary artery disease in the French population

Rosa-Maria Guéant-Rodriguez; Yves Juilliére; Mirande Candito; Charles E. Adjalla; Pierre Gibelin; Bernard Herbeth; Emmanuel Van Obberghen; Jean-Louis Guéant

doi:10.1160/TH05-04-0262

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(03): 510-515
DOI: 10.1160/TH05-04-0262

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Association of MTRR A66G polymorphism (but not of MTHFR C677T and A1298C, MTR A2756G, TCN C776G) with homocysteine and coronary artery disease in the French population

Rosa-Maria Guéant-Rodriguez

¹INSERM U-724, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine, Vandoeuvre-les-Nancy Cedex, France

²Department of Cardiology, University Hospital Center of Nancy, France

,

Yves Juilliére

¹INSERM U-724, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine, Vandoeuvre-les-Nancy Cedex, France

²Department of Cardiology, University Hospital Center of Nancy, France

,

Mirande Candito

³Departments of Biochemistry and Cardiology, University Hospital Center of Nice, France

,

Charles E. Adjalla

¹INSERM U-724, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine, Vandoeuvre-les-Nancy Cedex, France

,

Pierre Gibelin

³Departments of Biochemistry and Cardiology, University Hospital Center of Nice, France

,

Bernard Herbeth

⁴Centre de Médecine Préventive de Nancy, Vandoeuvre-les-Nancy, France

,

Emmanuel Van Obberghen

³Departments of Biochemistry and Cardiology, University Hospital Center of Nice, France

,

Jean-Louis Guéant

¹INSERM U-724, Laboratory of Cellular and Molecular Pathology in Nutrition, Faculty of Medicine, Vandoeuvre-les-Nancy Cedex, France

› Author Affiliations

Abstract

Summary

methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) is an established determinant of homocysteine plasma level (t-Hcys) while its association with coronary artery disease (CAD) seems to be more limited. In contrast, the association of the substitutions A2756G of methionine synthase (MTR), A66G of methionine synthase reductase (MTRR) and C776G of transcobalamin (TCN) to both t-Hcys and CAD needs to be evaluated further. The objective was to evaluate the association of these polymorphisms with t-Hcys and CAD in a French population. We investigated the individual and combined effects of these polymorphisms and of vitamin B12 and folates with t-Hcys in 530 CAD patients and 248 matched healthy controls. t-Hcys was higher in the CAD group than in controls (11.8 vs 10.4 μM, P<0.0001) and in carriers of MTRR AA and MTHFR 677TT than in those carrying the most frequent allele of both polymorphisms (13.8 vs 11.4 μM, P=0.0102 and 12.5 vs 11.0 mM, P=0.0065 respectively). The frequency of MTRR A allele was higher in CAD patients than in controls (0.48 [95% CI: 0.44-0.52] vs 0.38 [95% CI: 0.32-0.44], P=0.0081) while no difference was observed for MTHFR 677T frequency. In multivariate analysis, t-Hcys > median and MTRR AA genotype were two significant independent predictors of CAD with respective odds ratios of 3.1 (95 % CI: 1.8-5.1, P<0.0001) and 4.5 (95% CI: 1.5-13.1, P=0.0051). In conclusion, in contrast to North Europe studies, MTRR AA genotype is a genetic determinant of moderate hyperhomocysteinemia associated with CAD in a French population without vitamin fortification.

Keywords

Coronary artery disease - folate - homocysteine - methionine synthase reductase - transcobalamin - vitamin B12

Full Text

References

References
1 Wilcken EL, Wilcken B. The pathogenesis of Coronary Artery Disease: A possible role for the methionine metabolism.. J Clin Invest 1976; 57: 1079-82.
2 Clarke R, Daly L, Robinson K. Hyperhomocysteinemia: an independent risk factor for vascular disease.. N Engl J Med 1991; 324: 1149-55.
3 Malinow MR. Homocyst (e)ine and vascular occlusive disease.. Nutr Metab Cardiovasc Dis 1992; 1: 166-9.
4 Quinlivan EP, McPartlin J, McNulty H. et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease.. Lancet 2002; 359: 227-8.
5 Frosst P, Blom HJ, Milos R. et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.. Nat Genet 1995; 10: 111-3.
6 Chen J, Stampfer MJ, Ma J. et al. Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction.. Atherosclerosis 2001; 154: 667-72.
7 Leclerc D, Wilson A, Dumas R. et al. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients with homocystinuria.. Proc Natl Acad Sci U S A 1998; 95: 3059-64.
8 Namour F, Olivier J, Abdelmouttaleb I. et al. Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians: relation to transcobalamin and homocysteine concentration in blood.. Blood 2001; 97: 1092-8.
9 Goyette P, Christensen B, Rosenblatt DS. et al. 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.
10 Ueland PM, Hustad S, Schneede J. et al. Biological and clnical implications of the MTHFR C677T polymorphism.. Trends Pharmacol Sci 2001; 22: 195-201.
11 Kluijtmans LA, Kastelein JJ, Lindemans J. et al. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease.. Circulation 1997; 96: 2573-77.
12 Kosokabe T, Okumura K, Sone T. et al. Relation of a common methylenetetrahydrofolate reductase mutation and plasma homocysteine with intimal hyperplasia after coronary stenting.. Circulation 2001; 103: 2048-54.
13 Kluijtmans LA, Whitehead AS. Methylenetetrahydrofolate reductase genotypes and predisposition of atherothrombotic disease; evidence that three MTHFR C677T genotypes confer different levels of risk.. Eur Heart J 2001; 22: 294-9.
14 Ueland PM, Refsum H, Beresford SA. et al. The controversy over homocysteine and cardiovascular risk.. Am J Clin Nutr 2000; 72: 324-32.
15 Brattstrom L, Wilcken DE, Ohrvik J. et al. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis.. Circulation 1998; 98: 2520-6.
16 Girelli D, Frisso S, Trabetti E. et al. Methylenetetrahydrofolate reductase C677T mutation, plasma homocysteine, and folate in subjects from northern Italy with or without angiographically documented severe coronary atherosclerotic disease: evidence for an important genetic-environmental interaction.. Blood 1998; 91: 4158-63.
17 Akar N, Akar E, Akcay R. et al. Effect of methylenetetrahydrofolate reductase 677 C-T, 1298 A-C, and 1317 T-C on factor V 1691 mutation in Turkish deep vein thrombosis patients.. Thromb Res 2000; 97: 163-7.
18 van der Put NM, Gabreëls F, Stevens E. et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural tube defects ?. Am J Hum Genet 1998; 62: 1044-51.
19 Klerk M, Lievers KJ, Kluijtmans LA. et al. The 2756A >G variant in the gene encoding methionine synthase: its relation with plasma homocysteine levels and risk of coronary heart disease in a Dutch case-control study.. Thromb Res 2003; 110: 87-91.
20 Morita H, Kurihara H, Sugiyama T. et al. Polymorphism of the methionine synthase gene : association with homocysteine metabolism and late-onset vascular diseases in the Japanese population.. Arterioscler Thromb Vasc Biol 1999; 19: 298-302.
21 Zetterberg H, Coppola A, D’Angelo A. et al. No association between the MTHFR A1298C and transcobalamin C776G genetic polymorphisms and hyperhomocysteinemia in thrombotic disease.. Thromb Res 2002; 108: 127-31.
22 Barbé F, Abdelmouttaleb I. Chango et al. Detection of moderate hyperhomocysteinemia : Comparison of the Abbot fluorescence polarisation immunoassay with Bio-Rad and SBD-F high-performance liquid chromatografic assays.. Amino Acids 2001; 20: 435-40.
23 Anwar W, Guéant JL, Abdelmouttaleb I. et al. Hyperhomocysteinemia is related to residual glomerular filtration and folate, but not to methylenetetrahydrofolate- reductase and methionine synthase polymorphisms, in supplemented end-stage renal disease patients undergoing hemodialysis.. Clin Chem Lab Med 2001; 39: 747-52.
24 Meisel C, Cascorbi I, Gerloff T. et al. Identification of six methylenetetrahydrofolate reductase (MTHFR) genotypes resulting from common polymorphisms : impact on plasma homocysteine levels and development of coronary artery disease.. Atherosclerosis 2001; 154: 651-8.
25 Ford ES, Smith SJ, Stroup DF. et al. Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies.. Int J Epidemiol 2002; 31: 59-70.
26 Clarke R, Daly L, Robinson K. et al. Hyperhomocysteinemia: an independent risk factor for vascular disease.. N Engl J Med 1991; 324: 1149-55.
27 Wang XL, Cai H, Cranney G. et al. The frequency of a common mutation of the methionine synthase gene in the Australian population and its relation to smoking and coronary artery disease.. J Cardiovasc Risk 1998; 5: 289-95.
28 Brown CA, McKinney KQ, Kaufman JS. et al. A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease.. J Cardiovasc Risk 2000; 7: 197-200.
29 Hyndman ME, Bridge PJ, Warnica JW. et al. Effect of heterozygosity for the methionine synthase 2756 A ® G mutation on the risk for recurrent cardiovascular events.. Am J Cardiol 2000; 86: 1144-6.
30 Tsai MY, Bignell M, Yang F. et al. Polygenic influence on plasma homocysteine : association of two prevalent mutations, the 844ins68 of cystathionine B-synthase and A2756G of methionine synthase, with lowered plasma homocysteine levels.. Atherosclerosis 2000; 149: 131-7.
31 Gaughan DJ, Kluijtmans LA, Sandrine Barbaux S. et al. The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations.. Atherosclerosis 2001; 157: 451-6.
32 Wang WL, Duarte N, Cai H. et al. Relationship between total plasma homocysteine, polymorphisms of homocysteine metabolism related enzymes, risk factors and coronary artery disease in the Autralian hospital- based population.. Atherosclerosis 1999; 146: 133-140.
33 Vaughn JD, Bailey LB, Shelnutt KP. et al. Methionine Synthase Reductase 66A®G polymorphism is associated with increased plasma homocysteine concentration when combined with the homozygous Methylenetetrahydrofolate Reductase 677C®T variant.. J Nutr 2004; 134: 2985-90.
34 Kluijtmans LAJ, Young IS, Boreham CA. et al. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults.. Blood 2003; 101: 2483-8.
35 Feix A, Winkelmayer WC, Eberle C. et al. Methionine synthase reductase MTRR 66 A>G has no effect on total homocysteine, folate, and vitamin B12 concentrations in renal transplant patients.. Atherosclerosis 2004; 174: 43-8.
36 Brown CA, McKinney KQ, Kaufman JS. et al. A common polymorphism in methionine synthase reductase increases risk of premature coronary artery disease.. J Cardiovas Risk 2000; 7: 197-200.
37 Brilakis ES, Berger PB, Ballman KV. et al. Methylentetrahydrofolate reductase (MTHFR) 677 C>T and methionine synthase reductase (MTRR) 66 A>G polymorphisms: association with serum homocysteine and angiographic coronary artery disease in the era of flour products fortified with folic acid.. Atherosclerosis 2003; 168: 315-22.
38 de Bree A, Verschuren WM, Blom HJ. et al. Association between B vitamin intake and plasma homocysteine concentration in the general Dutch population aged 20–65 y.. Am J Clin Nutr 2001; 73: 1027-33.
39 Mennen LI, de Courcy GP, Guilland JC. et al. Homocysteine, cardiovascular disease risk factors, and habitual diet in the French Supplementation with Antioxidant Vitamins and Minerals Study.. Am J Clin Nutr 2002; 76: 1279-89.
40 Allen LH. Folate and vitamin B12 status in the Americas.. Nutr Rev 2004; 62: S29-33.
41 Miller JW, Ramos MI, Garrod MG. et al. Transcobalamin II 775 G>C polymorphism and indices of vitamin B12 status in healthy older adults.. Blood 2002; 100: 718-20.
42 Lievers KJ, Afman LA, Kluijtmans LA. et al. Polymorphisms in the transcobalamin gene: association with plasma homocysteine in healthy individuals and vascular disease patients.. Clin Chem 2002; 48: 1383-9.