Homocysteine levels and polymorphisms of MTHFR and CBS genes in Colombian patients with superficial and deep venous thrombosis
Keywords:
homocysteine, polymorphism, genetic, hyperhomocysteinemia, thrombosis, atherosclerosis, cystathionine beta-synthase
Abstract
Introduction. Thrombosis develops when the hemostatic system is incorrectly activated due to the unbalance between procoagulant, anticoagulant and fibrinolytic mechanisms allowing the formation of a clot within a blood vessel. The risk factors of this pathology can be acquired or can be genetic.Objectives. To analyze in a Colombian population with diagnosis of venous thrombosis, lipid profile, glucose and homocystein levels, to calculate the alleles and genotypic frequencies of polymorphisms c.699 C>T, c.1080 C>T, c.844ins68 of the cystathionine ß synthase and the c.677 C>T of the methylenetetrahydrofolate reductase (MTHFR) genes.
Materials and methods. Thirty three patients and their controls were studied. The biochemical test was carried out by colorimetric methods and immunoassay. In this survey we used the restriction fragments longitude polymorphism (RLFP) technique to identify the polymorphisms mentioned. The association study was performed through the chi square test.
Results. We confirmed that gene alterations increase risk for pathology; we found statistically significant differences in the group with hypercholesterolemia in presence of the polymorphism c.699 C>T in the CBS gene, showing a protective effect in the individuals carrying this genetic variation. Likewise, we found a statistical trend for an eventual protective effect of the CBS c.844ins68 polymorphism to venous thrombotic disease.
Conclusions. There were not any statistically significant differences in homocystein levels between cases and controls; nevertheless, the variability in the plasma concentrations was greater in the group of cases.
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References
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2. Kamphuisen PW, Eikenboom CC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol. 2001;21:731-8.
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12. Nadir Y, Hoffman R, Brenner B. Association of homocysteine, vitamin B12, folic acid, and MTHFR C677T in patients with a thrombotic event or recurrent fetal loss. Ann Hematol. 2007;86:35-40.
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14. Varga EA, Sturm AC, Misita CP, Moll S. Homocysteine and MTHFR mutations relation to thrombosis and coronary artery disease. Circulation. 2005;111:289-93.
15. Spiroski I, Kedev S, Antov S, Arsov T, Krstevska M, Dzhekova-Stojkova S, et al. Association of methylenetetrahydrofolate reductase (MTHFR-677 and MTHFR-1298) genetic polymorphisms with occlusive artery disease and deep venous thrombosis in Macedonians. Croat Med J. 2008;49:39-49.
16. Gemmati D, Serino ML, Trivellato C, Fiorini S, Scapoli GL. C677T substitution in the methylenetetrahydrofolate reductase gene as a risk factor for venous thrombosis and arterial disease in selected patients. Haematologica. 1999;84:824-8.
17. Bezemer ID, Doggen KJ, Vos HL, Rosendaal FR. No association between the common MTHFR 677C→T polymorphism and venous thrombosis. Arch Intern Med. 2007;167:497-501.
18. Orhan AL, Okuyan E, Okcun B, Nurkalem Z. Plasma homocysteine level and left ventricular thrombus formation in acute anterior myocardial infarction patients following thrombolytic therapy with t-PA. Thromb Res. 2009;124:65-9.
19. Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp S, Helmerhorst FM, Bouma BN, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med. 2001;344:1537-5.20. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol. 2002;22:201-10.
21. D'Angelo A, Mazzola G, Crippa L, Fermo I, D'Angelo SV. Hyperhomocysteinemia and venous thromboembolic disease. Haematologica. 1997;82:211-9.
22. Undas A, Brozek J, Jankowski M, Siudak Z, Szczeklik A, Jakubowski H. Plasma homocysteine affects fribrin clot permeability and resistance to lysis in human subjects. Arterioscler Thromb Vasc Biol. 2006;26:1397-04.
23. Sharma P, Senthilkumar RD, Brahmachari V, Sundaramoorthy E, Mahajan A, Sharma A, et al. Mining literature for a comprehensive pathway analysis: A case study for retrieval of homocysteine related genes for genetic and epigenetic studies. Lipids Health Dis. 2006;5:1-19.
24. Tsai MY, Bignell M, Yang F, Welge BG, Graham KJ, Hanson NQ. 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.
25. Lievers KJ, Kluijtmans LA, Blom HJ. Genetics of hyperhomocysteinaemia in cardiovascular disease. Ann Clin Biochem. 2003;40:46-59.
26. Grossman R, Schwender S, Geisen U, Schambeck C, Merati G, Walter U. CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein thrombosis. Thromb Res. 2002;107:13-5.
27. Bonini-Domingos CR, Zamaro PJ, Mendiburu CF, Sanchez FE, Cintra JR, de Godoy JM, et al. Frequency of the 844ins68 mutation on the cystathionine β-synthetase gene in deep venous thrombosis patients. Rev Bras Hematol Hemoter. 2005;1:12-5.
28. Franchis R, Fermo I, Mazzola G, Sebastio G, Di Minno G, Coppola A, et al. Contribution of the cystathionine b synthase gene (844ins68) polymorphism to the risk of early-onsent venous and arterial occlusive disease and of fasting hyperhomocysteinemia. Thromb Haemost. 2000;84:576-82.
29. Pezzini A, Zotto E, Archetti S, Negrini R, Bani P, Albertini A, et al. CBS genotype in young adults with spontaneous cervical artery dissection plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp and atherothrombotic stroke. Stroke. 2002;33:664-9.
30. Franco R, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Genet. 2001;109:369-84.
2. Kamphuisen PW, Eikenboom CC, Bertina RM. Elevated factor VIII levels and the risk of thrombosis. Arterioscler Thromb Vasc Biol. 2001;21:731-8.
3. Rosendaal FR. Venous thrombosis: the role of genes environment and behavior. Hematology. 2005;1:1-12.
4. Pendás JA, Estébanez RV. Trombosis venosa. Guías Clínicas. 2002; 26:1-5.
5. Doggen CJ, Smith NL, Lemaitre RN, Heckebert SR, Rosendaal FR, Psaty BM. Serum lipid levels and the risk of venous trombosis. Arterioscler Thromb Vasc Biol. 2004;24:1970-5.
6. Aznar J, Vaya A, Estellés A, Mira Y, Segui R, Villa P, et al. Risk of venous trombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives. Haematologica. 2000;85:1271-6.
7. Eldibany MM, Caprini JA. Hyperhomocysteinemia and thrombosis. Arch Pathol Lab Med. 2007;131:837-72.
8. Loscalzo J. Homocysteine-mediated thrombosis and angiostasis in vascular pathobiology. J Clin Invest. 2009;119:3203-5.
9. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62.
10. Bermúdez M, Briceño I, Gil F, Bernal J. Homocisteína y polimorfismos de la cistationina β sintasa y metilentetrahidrofolato-reductasa en población sana de Colombia. Colomb Med. 2006;37:46-52.
11. Fonseca V, Suba SC, Fink LM. Hyperhocysteinemia and the endocrine system: implications for atherosclerosis and trombosis. Endocr Rev. 1999;20:738-59.
12. Nadir Y, Hoffman R, Brenner B. Association of homocysteine, vitamin B12, folic acid, and MTHFR C677T in patients with a thrombotic event or recurrent fetal loss. Ann Hematol. 2007;86:35-40.
13. Alpert MA. Homocysteine, atherosclerosis and thrombosis. South Med J. 1999;92:858-64.
14. Varga EA, Sturm AC, Misita CP, Moll S. Homocysteine and MTHFR mutations relation to thrombosis and coronary artery disease. Circulation. 2005;111:289-93.
15. Spiroski I, Kedev S, Antov S, Arsov T, Krstevska M, Dzhekova-Stojkova S, et al. Association of methylenetetrahydrofolate reductase (MTHFR-677 and MTHFR-1298) genetic polymorphisms with occlusive artery disease and deep venous thrombosis in Macedonians. Croat Med J. 2008;49:39-49.
16. Gemmati D, Serino ML, Trivellato C, Fiorini S, Scapoli GL. C677T substitution in the methylenetetrahydrofolate reductase gene as a risk factor for venous thrombosis and arterial disease in selected patients. Haematologica. 1999;84:824-8.
17. Bezemer ID, Doggen KJ, Vos HL, Rosendaal FR. No association between the common MTHFR 677C→T polymorphism and venous thrombosis. Arch Intern Med. 2007;167:497-501.
18. Orhan AL, Okuyan E, Okcun B, Nurkalem Z. Plasma homocysteine level and left ventricular thrombus formation in acute anterior myocardial infarction patients following thrombolytic therapy with t-PA. Thromb Res. 2009;124:65-9.
19. Vandenbroucke JP, Rosing J, Bloemenkamp KW, Middeldorp S, Helmerhorst FM, Bouma BN, et al. Oral contraceptives and the risk of venous thrombosis. N Engl J Med. 2001;344:1537-5.20. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol. 2002;22:201-10.
21. D'Angelo A, Mazzola G, Crippa L, Fermo I, D'Angelo SV. Hyperhomocysteinemia and venous thromboembolic disease. Haematologica. 1997;82:211-9.
22. Undas A, Brozek J, Jankowski M, Siudak Z, Szczeklik A, Jakubowski H. Plasma homocysteine affects fribrin clot permeability and resistance to lysis in human subjects. Arterioscler Thromb Vasc Biol. 2006;26:1397-04.
23. Sharma P, Senthilkumar RD, Brahmachari V, Sundaramoorthy E, Mahajan A, Sharma A, et al. Mining literature for a comprehensive pathway analysis: A case study for retrieval of homocysteine related genes for genetic and epigenetic studies. Lipids Health Dis. 2006;5:1-19.
24. Tsai MY, Bignell M, Yang F, Welge BG, Graham KJ, Hanson NQ. 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.
25. Lievers KJ, Kluijtmans LA, Blom HJ. Genetics of hyperhomocysteinaemia in cardiovascular disease. Ann Clin Biochem. 2003;40:46-59.
26. Grossman R, Schwender S, Geisen U, Schambeck C, Merati G, Walter U. CBS 844ins68, MTHFR TT677 and EPCR 4031ins23 genotypes in patients with deep-vein thrombosis. Thromb Res. 2002;107:13-5.
27. Bonini-Domingos CR, Zamaro PJ, Mendiburu CF, Sanchez FE, Cintra JR, de Godoy JM, et al. Frequency of the 844ins68 mutation on the cystathionine β-synthetase gene in deep venous thrombosis patients. Rev Bras Hematol Hemoter. 2005;1:12-5.
28. Franchis R, Fermo I, Mazzola G, Sebastio G, Di Minno G, Coppola A, et al. Contribution of the cystathionine b synthase gene (844ins68) polymorphism to the risk of early-onsent venous and arterial occlusive disease and of fasting hyperhomocysteinemia. Thromb Haemost. 2000;84:576-82.
29. Pezzini A, Zotto E, Archetti S, Negrini R, Bani P, Albertini A, et al. CBS genotype in young adults with spontaneous cervical artery dissection plasma homocysteine concentration, C677T MTHFR genotype, and 844ins68bp and atherothrombotic stroke. Stroke. 2002;33:664-9.
30. Franco R, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Genet. 2001;109:369-84.
How to Cite
1.
Ayala C, García R, Cruz E, Prieto K, Bermúdez M. Homocysteine levels and polymorphisms of MTHFR and CBS genes in Colombian patients with superficial and deep venous thrombosis. biomedica [Internet]. 2010 Aug. 4 [cited 2024 May 16];30(2):259-67. Available from: https://revistabiomedica.org/index.php/biomedica/article/view/189
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