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DOI: 10.1160/TH06-02-0082
Association of homocysteine (but not of MTHFR 677 C>T, MTR 2756 A>G, MTRR 66 A>G and TCN2 776 C>G) with ischaemic cerebrovascular disease in Sicily
Publikationsverlauf
Received
11. Februar 2006
Accepted after resubmission
13. Juni 2006
Publikationsdatum:
28. November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200602/lookinside/thumbnails/10-1160-th06-02-0082-1.jpg)
Summary
Association between methylenetetrahydrofolate reductase polymorphism (MTHFR 677 C>T), a determinant of homocysteine plasma level (t-Hcys), with ischaemc cerebrovascular disease (iCVD) seems to be neutral in North Europe and North America. The association of 2756 A>G of methionine synthase (MTR), 66 A>G of methionine synthase reductase (MTRR) and 776 C>G of transcobalamin (TCN2) needs to be evaluated further. It was the objective of this study to evaluate the association of these polymorphisms, t-Hcys, vitamin B12 and folate levels with iCVD, in an Italian population from Sicily. We investigated the association of these polymorphisms, t-Hcys, vitamin B12 and folate with iCVD in 252 subjects, including 131 cases and 121 sexand agematched healthy controls. t-Hcys was higher in the iCVD group than in controls [15.3 (11.5–17.9) vs. 11.6 (9.4–14.5) µM; P=0. 0007] and also in subjects withTCN2 776CG genotype, compared to homozygous genotypes [13.5 (9.9± 16.9) vs. 11.7 (9.6 ± 14.4) µM; P=0. 0327]. The folate level in cases and controls was consistent with an adequate dietary intake [12.7 (9.0–15.3) vs. 12.5 (9.6–16.9) nM; P=0. 7203]. In multivariate analysis, t-Hcys was a significant independent predictor of iCVD with an odds ratio of 1.14 (95% C.I. : 1.06–1.24; P=0. 0006). No association was found between MTHFR, MTR, MTRR and TCN2 polymorphisms and iCVD risk. We have found an influence of t-Hcys and a neutral effect of MTHFR, MTR, MTRR and TCN2 on iCVD risk in Sicily. The neutral influence of these polymorphisms may be explained by adequate status in folate and vitamin B12. Other factors underlying the increased t-Hcys need further investigations.
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References
- 1 Adams RD, Victor M, Ropper AH. Principles of Neurology. 6th ed. New York: McGraw Hill; 1997
- 2 Allen CMC, Lueck CJ. Davidson’s principles and practice of medicine. In: Cerebrovascular diseases. 19th ed. London: Churchill Livingstone; 2002: 1159-68.
- 3 Roman GC, Tatemichi TK, Erkinjuntti T. et al. Vascular dementia: diagnostic criteria for research studies: report of the NINDS-AIREN international workshop. Neurology 1993; 43: 250-60.
- 4 Chapman J, Wang N, Treves TA. et al. ACE, MTHFR, Factor V Leiden and APOE polymorphisms in patients with vascular and Alzheimer’s dementia. Stroke 1998; 29: 1401-4.
- 5 Catto A, Carter AM, Barrett JH. et al. Angiotensin-converting enzyme insertion/deletion polymorphism and cerebrovascular disease. Stroke 1996; 27: 435-40.
- 6 Bollander-Gouaille C. Focus on homocysteine and the vitamins involved in its metabolism. 2nd ed. Paris: Spinger-Verlag; 2002
- 7 Undas A, Brozek J, Szczeklik A. Homocysteine and thrombosis: from basic science to clinical evidence. Thromb Haemost 2005; 94: 907-15.
- 8 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.
- 9 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.
- 10 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 USA 1998; 95: 3059-64.
- 11 Rosenblatt DS, Fenton WA. Inherited disorders of folate and cobalamin transport and metabolism. In: The metabolic and molecular bases of inherited disease. 8th ed. New York: Mc Graw Hill; 2001: 3897-933.
- 12 Ueland PM, Hustad S, Schneede J. et al. Biological and clinical implications of the MTHFR C677T polymorphism. Trends Pharmacol Sci 2001; 22: 195-201.
- 13 Kluijtmans LA, Kastelein JJ, Lindemans J. et al. Thermolabile methylenetetrahydrofolate reductase in coronary artery disease. Circulation 1997; 96: 2573-7.
- 14 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.
- 15 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 ina Dutch case-control study. Thromb Res 2003; 110: 87-91.
- 16 Guéant-Rodriguez RM, Juillière Y, Candito M. et al. Association of MTRR A66G polymorphism (but not of MTHFR C677T and A1298C, MTR A2756G, TCN2 C776G) with homocysteine and coronary artery disease in the French population. Thromb Haemost 2005; 94: 510-5.
- 17 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.
- 18 Pezzini A, Del Zotto E, Archetti S. et al. Plasma homocysteine concentration, C677T MTHFR genotype and 844ins68bp CBS genotype in young adults with spontaneous cervical artery dissection and atherothrombotic stroke. Stroke 2002; 33: 664-9.
- 19 Gallai V, Caso V, Paciaroni M. et al. Mild hyperhomocyst(e)inemia: a possible risk factor for cervical artery dissection. Stroke 2001; 32: 714-8.
- 20 Duca F, Sacchi E, Tagliabue L. et al. C677T methylenetetrahydrofolate reductase (MTHFR) mutation in stroke. Thromb Haemost 1997; 78 (Suppl): 102.
- 21 Margaglione M, D’Andrea G, Giuliani N. et al. Inherited prothrombotic conditions and premature ischemic stroke: sex difference in the association with factor V Leiden. Arterioscler Thromb Vasc Biol 1999; 19: 1751-6.
- 22 Cronin S, Furie K, Kelly P. Dose-related association of MTHFR 677T allele with risk of ischemic stroke: evidence from a cumulative meta-analysis. Stroke 2005; 36: 1581-7.
- 23 Guéant JL, Guéant-Rodriguez RM, Anello G. et al. Genetic determinants of folate and vitamin B12 metabolism: a common pathway in neural tube defect and Down syndrome?. Clin Chem Lab Med 2003; 41: 1473-7.
- 24 Barbé F, Abdelmouttaleb I, Chango A. 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.
- 25 Anwar W, Guéant JL, Abdelmouttaleb I. et al. Hyperhomocysteinemia is related to residual glomerular filtration and folate, but not to methylenetetrahydro-folate-reductase and methionine synthase polymorphisms, in supplemented end-stage renal disease patients undergoing hemodialysis. Clin Chem Lab Med 2001; 39: 747-52.
- 26 Lewis SJ, Ebrahim S, Smith GD. Meta-analysis of MTHFR 677C>T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?. Br Med J 2005; 331: 1053.
- 27 Klerk M, Verhoef P, Clarke R. et al. MTHFR 677C>T polymorphism and risk of coronary heart disease: a meta-analysis. J Am Med Assoc 2002; 288: 2023-31.
- 28 Kelly PJ, Shih VE, Kistler JP. et al. Low vitamin B6, but not homocyst(e)ine, is associated with increased risk of stroke/TIA in the era of folic acid grain fortification. Stroke 2003; 34: e51-4.
- 29 Guéant-Rodriguez RM, Guéant JL, Debard R. et al. Prevalence of methylenetetrahydrofolate reductase 677T and 1298C alleles and folate status: a comparative study among Mexican, West African and West European populations. Am J Clin Nutr 2006; 03: 701-7.
- 30 Turrini A, Saba A, Perrone D. et al. Food consumption patterns in Italy: the INN-CA Study 1994?1996. Eur J Clin Nutr 2001; 55: 571-88.
- 31 Panza F, D’Introno A, Colacicco AM. et al. Vascular genetic factors and human longevity. Mech Ageing Dev 2004; 125: 169-78.
- 32 Tsai MY, Bignell M, Yang F. et al. Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine β-synthase and A2756G of methionine synthase, with lowered plasma homocysteine levels. Atherosclerosis 2000; 149: 131-7.
- 33 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 Australian hospital-based population. Atherosclerosis 1999; 146: 133-40.
- 34 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; 05: 289-95.
- 35 Gaughan DJ, Kluijtmans LA, Sandrine SBarbaux. et al. The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis 2001; 157: 451-6.
- 36 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.
- 37 Kluijtmans LAJ, Young IS, Boreham CA. et al. Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults. Blood 2003; 101: 2483-8.
- 38 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; 07: 197-200.
- 39 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.
- 40 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.
- 41 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.
- 42 Guéant JL, Xiaohong L, Ortiou S. et al. The association between plasma homocysteine and holotranscobalamin and the transcobalamin 776C>G polymorphism is influenced by folate in the absence of supplementation and fortified diet. Am J Clin Nutr 2006; 83: 171-2.