Abstract
VKORC1 genetic polymorphisms affect warfarin dose response, aortic calcification, and the susceptibility of coronary artery disease as shown in our previous study. Little is known regarding the association of VKORC1 polymorphisms with coronary artery calcification (CAC) and the role of CAC in the association with coronary artery disease (CAD). Due to a natural haplotype block in the VKORC1 gene in Chinese, polymorphism rs2359612 was analyzed in a case–control study and a prospective study. The case–control study included 464 CAD patients with non-calcified plaque (NCP), 562 CAD patients with mixed calcified plaque (MCP), 492 subjects with calcified plaque (CP), and 521 controls. The rs2359612C was only associated with increased risk of MCP, the CAD in the presence of CAC; the odds ratio was 1.397 (95 % CI 1.008–1.937, P < 0.05), which was replicated in the second independent population. On the contrary, a negative correlation was observed between rs2359612 and log-transformed Agatston score, and rs2359612 was negatively associated with the number of calcified vessels. Moreover, in a prospective study including 849 CAD patients undergoing revascularization, rs2359612C predicted a higher incidence of cardiovascular events in MCP subgroup; the relative risk was 1.435 (95 % CI 1.008–2.041, P = 0.045), which was not observed in the NCP subgroup. We conclude that the rs2359612C was associated with a higher risk of CAD in the presence of CAC and a higher incidence of cardiovascular events in CAD patients with CAC, but a lower coronary calcification. VKORC1 polymorphisms may be associated with the endophenotype of CAD, calcification-related atherosclerosis.
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References
Aikawa E, Nahrendorf M, Figueiredo JL, Swirski FK, Shtatland T, Kohler RH, Jaffer FA, Aikawa M, Weissleder R (2007) Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation 116:2841–2850. doi:10.1161/CIRCULATIONAHA.107.732867
Arnold ML, Lichy C, Werner I, Radbruch A, Wagner S, Grond-Ginsbach C (2008) Single nucleotide polymorphisms in the VKORC1 gene and the risk of stroke in the Southern German population. Thromb Haemost 100:614–617 pii: 08100614
Borissoff JI, Heeneman S, Kilinc E, Kassak P, Van Oerle R, Winckers K, Govers-Riemslag JW, Hamulyak K, Hackeng TM, Daemen MJ, ten Cate H, Spronk HM (2010) Early atherosclerosis exhibits an enhanced procoagulant state. Circulation 122:821–830. doi:10.1161/CIRCULATIONAHA.109.907121
Budoff MJ, Achenbach S, Blumenthal RS, Carr JJ, Goldin JG, Greenland P, Guerci AD, Lima JA, Rader DJ, Rubin GD, Shaw LJ, Wiegers SE (2006) Assessment of coronary artery disease by cardiac computed tomography: a scientific statement from the American Heart Association Committee on Cardiovascular Imaging and Intervention, Council on Cardiovascular Radiology and Intervention, and Committee on Cardiac Imaging, Council on Clinical Cardiology. Circulation 114:1761–1791. doi:10.1161/CIRCULATIONAHA.106.178458
Burns P, Hoffman CJ, Katz JP, Miller RH, Lawson WE, Hultin MB (1993) Vitamin K-dependent clotting factors are elevated in young adults who have close relatives with ischemic heart disease. J Lab Clin Med 122:720–727 pii: 0022-2143(93)90255-W
Chatrou ML, Reutelingsperger CP, Schurgers LJ (2011) Role of vitamin K-dependent proteins in the arterial vessel wall. Hamostaseologie 31:251–257. doi:10.5482/ha-1157
D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, Grandone E, Margaglione M (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105:645–649. doi:10.1182/blood-2004-06-2111
de Visser MC, Roshani S, Rutten JW, van Hylckama Vlieg A, Vos HL, Rosendaal FR, Reitsma PH (2011) Haplotypes of VKORC1, NQO1 and GGCX, their effect on activity levels of vitamin K-dependent coagulation factors, and the risk of venous thrombosis. Thromb Haemost 106:563–565. doi:10.1160/TH11-05-0339
Esmon CT (2003) Inflammation and thrombosis. J Thromb Haemost 1:1343–1348. doi:261
Esmon CT (2005) The interactions between inflammation and coagulation. Br J Haematol 131:417–430. doi:10.1111/j.1365-2141.2005.05753.x
Hindorff LA, Heckbert SR, Smith N, Marciante KD, Psaty BM (2007) Common VKORC1 variants are not associated with arterial or venous thrombosis. J Thromb Haemost 5:2025–2027. doi:10.1111/j.1538-7836.2007.02705.x
Idelevich A, Rais Y, Monsonego-Ornan E (2011) Bone Gla protein increases HIF-1alpha-dependent glucose metabolism and induces cartilage and vascular calcification. Arterioscler Thromb Vasc Biol 31:e55–e71. doi:10.1161/ATVBAHA.111.230904
Leber AW, Becker A, Knez A, von Ziegler F, Sirol M, Nikolaou K, Ohnesorge B, Fayad ZA, Becker CR, Reiser M, Steinbeck G, Boekstegers P (2006) Accuracy of 64-slice computed tomography to classify and quantify plaque volumes in the proximal coronary system: a comparative study using intravascular ultrasound. J Am Coll Cardiol 47:672–677. doi:10.1016/j.jacc.2005.10.058
Levi M, van der Poll T, Buller HR (2004) Bidirectional relation between inflammation and coagulation. Circulation 109:2698–2704. doi:10.1161/01.CIR.0000131660.51520.9A
Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW (2004) Identification of the gene for vitamin K epoxide reductase. Nature 427:541–544. doi:10.1038/nature02254
Lu JG, Lv B, Chen XB, Tang X, Jiang SL, Dai RP (2010) What is the best contrast injection protocol for 64-row multi-detector cardiac computed tomography? Eur J Radiol 75:159–165. doi:10.1016/j.ejrad.2009.04.035
Min JK, Edwardes M, Lin FY, Labounty T, Weinsaft JW, Choi JH, Delago A, Shaw LJ, Berman DS, Budoff MJ (2011) Relationship of coronary artery plaque composition to coronary artery stenosis severity: results from the prospective multicenter ACCURACY trial. Atherosclerosis 219:573–578. doi:10.1016/j.atherosclerosis.2011.05.032
Musunuru K, Post WS, Herzog W, Shen H, O’Connell JR, McArdle PF, Ryan KA, Gibson Q, Cheng YC, Clearfield E, Johnson AD, Tofler G, Yang Q, O’Donnell CJ, Becker DM, Yanek LR, Becker LC, Faraday N, Bielak LF, Peyser PA, Shuldiner AR, Mitchell BD (2010) Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity: a potential mechanism for increased vascular disease. Circ Cardiovasc Genet 3:445–453. doi:10.1161/CIRCGENETICS.109.923508
Nadra I, Mason JC, Philippidis P, Florey O, Smythe CD, McCarthy GM, Landis RC, Haskard DO (2005) Proinflammatory activation of macrophages by basic calcium phosphate crystals via protein kinase C and MAP kinase pathways: a vicious cycle of inflammation and arterial calcification? Circ Res 96:1248–1256. doi:10.1161/01.RES.0000171451.88616.c2
Pasmant E, de Beauvoir C, Plessier A, Labreuche J, Bezeaud A (2010) VKORC1 and CYP2C9 genetic polymorphisms in hepatic or portal vein thrombosis. Thromb Res 126:e134–e136. doi:10.1016/j.thromres.2010.03.015
Pechlivanis S, Scherag A, Muhleisen TW, Mohlenkamp S, Horsthemke B, Boes T, Brocker-Preuss M, Mann K, Erbel R, Jockel KH, Nothen MM, Moebus S (2010) Coronary artery calcification and its relationship to validated genetic variants for diabetes mellitus assessed in the Heinz Nixdorf recall cohort. Arterioscler Thromb Vasc Biol 30:1867–1872. doi:10.1161/ATVBAHA.110.208496
Rennenberg RJ, de Leeuw PW, Kessels AG, Schurgers LJ, Vermeer C, van Engelshoven JM, Kemerink GJ, Kroon AA (2010) Calcium scores and matrix Gla protein levels: association with vitamin K status. Eur J Clin Invest 40:344–349. doi:10.1111/j.1365-2362.2010.02275.x
Reyes-Garcia R, Rozas-Moreno P, Jimenez-Moleon JJ, Villoslada MJ, Garcia-Salcedo JA, Santana-Morales S, Munoz-Torres M (2012) Relationship between serum levels of osteocalcin and atherosclerotic disease in type 2 diabetes. Diabetes Metab 38:76–81. doi:10.1016/j.diabet.2011.07.008
Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285–2293. doi:10.1056/NEJMoa044503
Rost S, Fregin A, Ivaskevicius V, Conzelmann E, Hortnagel K, Pelz HJ, Lappegard K, Seifried E, Scharrer I, Tuddenham EG, Muller CR, Strom TM, Oldenburg J (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427:537–541. doi:10.1038/nature02214
Rubin J, Chang HJ, Nasir K, Blumenthal RS, Blaha MJ, Choi EK, Chang SA, Yoon YE, Chun EJ, Choi SI, Agatston AS, Rivera JJ (2011) Association between high-sensitivity C-reactive protein and coronary plaque subtypes assessed by 64-slice coronary computed tomography angiography in an asymptomatic population. Circ Cardiovasc Imaging 4:201–209. doi:10.1161/CIRCIMAGING.109.929901
Smadja DM, Loriot MA, Hindorff LA, Mellottee L, Gaussem P, Emmerich J (2008) No clear link between VKORC1 genetic polymorphism and the risk of venous thrombosis or peripheral arterial disease. Thromb Haemost 99:970–972. doi:10.1160/TH07-12-0742
Stafford DW (2005) The vitamin K cycle. J Thromb Haemost 3:1873–1878. doi:10.1111/j.1538-7836.2005.01419.x
Stenflo J, Fernlund P, Egan W, Roepstorff P (1974) Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci USA 71:2730–2733
Teichert M, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, De Smet PA, Witteman JC, Stricker BH (2008) Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphism and aortic calcification: the Rotterdam Study. Arterioscler Thromb Vasc Biol 28:771–776. doi:10.1161/ATVBAHA.107.159913
Wang Y, Zhen Y, Shi Y, Chen J, Zhang C, Wang X, Yang X, Zheng Y, Liu Y, Hui R (2005) Vitamin K epoxide reductase: a protein involved in angiogenesis. Mol Cancer Res 3:317–323. doi:10.1158/1541-7786.MCR-04-0221
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 (2006) VKORC1 haplotypes are associated with arterial vascular diseases (stroke, coronary heart disease, and aortic dissection). Circulation 113:1615–1621. doi:10.1161/CIRCULATIONAHA.105.580167
Weijs B, Blaauw Y, Rennenberg RJ, Schurgers LJ, Timmermans CC, Pison L, Nieuwlaat R, Hofstra L, Kroon AA, Wildberger J, Crijns HJ (2011) Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. Eur Heart J 32:2555–2562. doi:10.1093/eurheartj/ehr226
Xu N, Dahlback B, Ohlin AK, Nilsson A (1998) Association of vitamin K-dependent coagulation proteins and C4b binding protein with triglyceride-rich lipoproteins of human plasma. Arterioscler Thromb Vasc Biol 18:33–39
Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, Lu MJ, Hung CR, Wei CY, Chen CH, Wu JY, Chen YT (2005) A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 14:1745–1751. doi:10.1093/hmg/ddi180
Acknowledgments
We are indebted to the participants in the study and their families for their outstanding commitment and cooperation. The study was supported by National Natural Science Foundation of China with grant 31171220 (Dr. Wang), Ministry of Science and Technology of China with grants 973 2012CB517804 (Dr. Wang) and 2011BAI11B04 (Dr. Hui), and National Natural Science Foundation of China with grant 30800619 (Dr. Wang).
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Wang, Y., Chen, J., Zhang, Y. et al. VKORC1 rs2359612C allele is associated with increased risk of coronary artery disease in the presence of coronary calcification. Hum Genet 132, 29–37 (2013). https://doi.org/10.1007/s00439-012-1222-y
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DOI: https://doi.org/10.1007/s00439-012-1222-y