Biopolym. Cell. 2015; 31(1):46-56.
Biomedicine
Association of allelic polymorphisms of the Matrix Gla-protein system genes with acute coronary syndrome in the Ukrainian population
1Garbuzova V. Yu., 2Stroy D. A., 2Dosenko V. E., 1Obukhova O. A., 1Ataman O. V.
  1. Sumy State University
    2, Rymskogo-Korsakova., Sumy, Ukraine, 40007
  2. O. O. Bogomoletz Institute of Physiology, NAS of Ukraine
    Akademika Bogomoltsa Str., 4, Kyiv, Ukraine, 01004

Abstract

Calcification of the vascular wall is a prognostic factor for the outcome of acute coronary syndrome (ACS). Matrix Gla-protein system, which includes MGP, VDR, VKOR, GGCX, BMP-2 is an important factor in vessels protection of ectopic calcification. Polymorphisms of genes, which encode the structure of these proteins, determine their activity and may affect the intensity of calcification and the consequences of ACS. Aim. The association between ACS and polymorphic variants of Matrix Gla-protein system genes: MGP (rs1800802, rs1800801, rs4236), VDR (rs2228570, rs1544410, rs7975232, rs731236), GGCX (rs699664), VKORC1 (rs2359612), BMP-2 (rs2273073), was analyzed. Methods. Venous blood of 118 patients with ACS and 234 healthy individuals (control group) was used for genotyping. Polymorphisms of Matrix Gla-protein system genes were examined by PCR-RFLP methodology. Results. The risk of ACS in carriers of minor allele A/A (rs1800801) is 2.8 times higher; G/G (rs1544410) 2.1 times higher; A (rs699664) and C (rs2359612) 2 times higher than in carriers of the major allele. The best classification model is a two-component model that includes polymorphisms rs1800801 and rs4236 of the MGP gene (predictive ability is 63 % for MDR and 68 % for the Random forest method). The coincidence of similar orientation genotype variants for chosen polymorphism was associated with a high risk of developing ACS: in the heterozygote genotype it increased by 2.1 times, and in the homozygote for the minor allele genotype, by 6.3 times. Conclusion. There is an association between ACS and some polymorphic variants of Matrix Gla-protein system genes: MGP (rs1800801), VDR (rs1544410), GGCX (rs699664), VKORC1 (rs2359612). This indicates a higher risk of complications in the ACS patients with the following genotypes: A/A (rs1800801), G/G (rs1544410), A/A (rs699664) and C/C (rs2359612).
Keywords: acute coronary syndrome, allelic polymorphism, matrix Gla-protein

References

[1] Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol. 2004;24(7):1161-70.
[2] Atkinson J. Age-related medial elastocalcinosis in arteries: mechanisms, animal models, and physiological consequences. J Appl Physiol (1985). 2008;105(5):1643-51.
[3] Dao HH, Essalihi R, Bouvet C, Moreau P. Evolution and modulation of age-related medial elastocalcinosis: impact on large artery stiffness and isolated systolic hypertension. Cardiovasc Res. 2005;66(2):307-17.
[4] Guzman RJ. Clinical, cellular, and molecular aspects of arterial calcification. J Vasc Surg. 2007;45 Suppl A:A57-63.
[5] Lanzer P. [M?nckeberg media calcinosis]. Z Kardiol. 1998;87(8):586-93.
[6] Lehto S, Niskanen L, Suhonen M, R?nnemaa T, Laakso M. Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mel­litus. Arterioscler Thromb Vasc Biol. 1996; 16 (8):978–83.
[7] Wayhs R, Zelinger A, Raggi P. High coronary artery calcium scores pose an extremely elevated risk for hard events. J Am Coll Cardiol. 2002;39(2):225-30.
[8] Garbuzova VYu, Ataman AV. Matrix Gla-protein and its role in vascular calcification. Int J Physiol Pathophysiol. 2012; 3(1):79–99.
[9] Proudfoot D, Shanahan CM. Molecular mechanisms mediating vascular calcification: role of matrix Gla protein. Nephrology (Carlton). 2006;11(5):455-61.
[10] Weissen-Plenz G, Nitschke Y, Rutsch F. Mechanisms of arterial calcification: spotlight on the inhibitors. Adv Clin Chem. 2008;46:263-93.
[11] Shao JS, Cheng SL, Sadhu J, Towler DA. Inflammation and the osteogenic regulation of vascular calcification: a review and perspective. Hypertension. 2010;55(3):579-92.
[12] Garbuzova VY, Gurianova VL, Stroy DA, Dosenko VE, Parkhomenko AN, Ataman AV. Association of matrix Gla protein gene allelic polymorphisms (G(-7)?A, T(-138)?C and Thr(83)?Ala) with acute coronary syndrome in the Ukrainian population. Exp Clin Cardiol. 2012 Spring;17(1):30-3.
[13] Ataman AV, Garbuzova VYu, Ataman YuA, Matlaj OI, Obu­khova OA. Investigation of the MGP promoter and exon 4 polymorphisms in patients with ischemic stroke in the Uk­rainian population. J Cell Mol Biol. 2012; 10(1):19–26.
[14] Brancaccio D, Biondi ML, Gallieni M, Turri O, Galassi A, Cecchini F, Russo D, Andreucci V, Cozzolino M. Matrix GLA protein gene polymorphisms: clinical correlates and cardiovascular mortality in chronic kidney disease patients. Am J Nephrol. 2005;25(6):548-52.
[15] Crosier MD, Booth SL, Peter I, Dawson-Hughes B, Price PA, O'Donnell CJ, Hoffmann U, Williamson MK, Ordovas JM. Matrix Gla protein polymorphisms are associated with coronary artery calcification in men. J Nutr Sci Vitaminol (Tokyo). 2009;55(1):59-65.
[16] Herrmann SM, Whatling C, Brand E, Nicaud V, Gariepy J, Simon A, Evans A, Ruidavets JB, Arveiler D, Luc G, Tiret L, Henney A, Cambien F. Polymorphisms of the human matrix gla protein (MGP) gene, vascular calcification, and myocardial infarction. Arterioscler Thromb Vasc Biol. 2000;20(11):2386-93.
[17] Kobayashi N, Kitazawa R, Maeda S, Schurgers L, Kitazawa S. T-138C polymorphism of matrix gla protein promoter alters its expression but is not directly associated with atherosclerotic vascular calcification. Kobe J Med Sci. 2004;50(3–4):69–81.
[18] Taylor BC, Schreiner PJ, Doherty TM, Fornage M, Carr JJ, Sidney S. Matrix Gla protein and osteopontin genetic associations with coronary artery calcification and bone density: the CARDIA study. Hum Genet. 2005;116(6):525-8.
[19] Kim JG, Ku SY, Lee DO, Jee BC, Suh CS, Kim SH, Choi YM, Moon SY. Relationship of osteocalcin and matrix Gla protein gene polymorphisms to serum osteocalcin levels and bone mineral density in postmenopausal Korean women. Menopause. 2006;13(3):467-73.
[20] Tsukamoto K, Orimo H, Hosoi T, Miyao M, Yoshida H, Watanabe S, Suzuki T, Emi M. Association of bone mineral density with polymorphism of the human matrix Gla protein locus in elderly women. J Bone Miner Metab. 2000;18(1):27-30.
[21] Gao B, Yasui T, Itoh Y, Tozawa K, Hayashi Y, Kohri K. A polymorphism of matrix Gla protein gene is associated with kidney stones. J Urol. 2007;177(6):2361-5.
[22] Hirano H, Ezura Y, Ishiyama N, Yamaguchi M, Nasu I, Yoshida H, Suzuki T, Hosoi T, Emi M. Association of natural tooth loss with genetic variation at the human matrix Gla protein locus in elderly women. J Hum Genet. 2003;48(6):288-92.
[23] Shaik AP, Jamil K. Individual susceptibility and genotoxicity in workers exposed to hazardous materials like lead. J Hazard Mater. 2009;168(2-3):918-24.
[24] Shaik AP, Jamil K. Polymorphisms in MGP gene and their association with lead toxicity. Toxicol Mech Methods. 2009;19(3):209-13.
[25] Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith EE 3rd, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Eagle KA, Faxon DP, Fuster V, Gardner TJ, Gregoratos G, Russell RO, Smith SC Jr. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee on the management of patients with unstable angina). Circulation. 2000;102(10):1193-209.
[26] Bertrand ME, Simoons ML, Fox KA, Wallentin LC, Hamm CW, McFadden E, De Feyter PJ, Specchia G, Ruzyllo W; Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2002;23(23):1809-40.
[27] Breiman L, Friedman JH, Olshen RA. Classification and re­gression trees. Belmont: C. A. «Wadsworth», 1984; 368 p.
[28] Breiman L. Random Forests. Machine Learning. 2001; 45 (1):5–32.
[29] Strobl C, Boulesteix AL, Kneib T, Augustin T, Zeileis A. Conditional variable importance for random forests. BMC Bioinformatics. 2008;9:307.
[30] Motsinger AA, Ritchie MD. Multifactor dimensionality reduction: an analysis strategy for modelling and detecting gene-gene interactions in human genetics and pharmacogenomics studies. Hum Genomics. 2006;2(5):318-28.
[31] Ortlepp JR, Krantz C, Kimmel M, von Korff A, Vesper K, Schmitz F, Mevissen V, Janssens U, Franke A, Hanrath P, Zerres K, Hoffmann R. Additive effects of the chemokine receptor 2, vitamin D receptor, interleukin-6 polymorphisms and cardiovascular risk factors on the prevalence of myocardial infarction in patients below 65 years. Int J Cardiol. 2005;105(1):90-5. ttp://
[32] Shanker J, Maitra A, Arvind P, Nair J, Dash D, Manchiganti R, Rao VS, Radhika KN, Hebbagodi S, Kakkar VV. Role of vitamin D levels and vitamin D receptor polymorphisms in relation to coronary artery disease: the Indian atherosclerosis research study. Coron Artery Dis. 2011;22(5):324-32.
[33] Pan XM, Li DR, Yang L, Wang EY, Chen TY, Liu YJ, Liu M, Liao ZG. No association between vitamin D receptor polymorphisms and coronary artery disease in a Chinese population. DNA Cell Biol. 2009;28(10):521-5.
[34] Porojan M, Dumitra?cu DL. Genetic polymorphism of VKORC 1 and KLOTHO genes associated with atherosclerosis. Clujul Medical. 2014; 85(4):533–6.
[35] Wang Y, Zhang W, Zhang Y, Yang Y, Sun L, Hu S, Chen J, Zhang C, Zheng Y, Zhen Y, Sun K, Fu C, Yang T, Wang J, Sun J, Wu H, Glasgow WC, Hui R. VKORC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection). Circulation. 2006;113(12):1615-21.
[36] Hindorff LA, Heckbert SR, Smith N, Marciante KD, Psaty BM. Common VKORC1 variants are not associated with arterial or venous thrombosis. J Thromb Haemost. 2007;5(10):2025-7.