Correlation of Warfarin Dosage and Genetic Polymorphism of Han-patients after Heart Valve Replacement_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANGYu-qing ^1,2 ,  DONGLi ¹ , SHIYing-kang ¹ , HOUJiang-long ¹ , JIANGHong ³ , FUBo ¹

1. Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;
2. Department of Thoracic Surgery, The Third Hospital of Jinan, Jinan 250132, P. R. China;
3. Department of Experiment, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

DONGLi, Email: donglikn199@163.com

Keywords：

Heart valve replacement; Oral anticoagulant therapy; Warfarin; Gene polymorphism

DOI：

10.7507/1007-4848.20160001

Video：

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Objectives To investigate the correlation of warfarin dose genetic and polymorphism of Han-patients after heart valve replacement, to forecast the anticoagulation therapy with warfarin reasonable dosage, and to realize individualized management of anticoagulation monitoring. Methods We selected 103 patients between January 1, 2011 and December 31, 2012 in West China Hospital of Sichuan University who were treated by oral warfarin after heart valve replacement with monitoring anticoagulation by international normalized ratio (INR) in Anticoagulation Therapy Database of Chinese Patients after Heart Valve Replacement. There were 32 males and 71 female at age of 21-85 (48.64± 11.66) years. All the patients' CYP2C9 and VKORC1 genetic polymorphisms were detected by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RELP) method and gene sequencing technology. Warfarin concentration in plasma was determined by high performance liquid chromatography (HPLC) method. The activity of coagulation factorⅡ, Ⅶ, Ⅸ, Ⅹwas determined by Sysmex CA7000 analyzer. Results The multivariate linear regression analysis showed that age, body surface area, and coagulation factor activity had no significant effect on warfarin dosage. While the gene polymor-phisms of CYP2C9 and VKORC1, warfarin concentration, and age had significant contributions to the overall variability in warfarin dose with decisive coefficients at 1.2%, 26.5%, 43.4%, and 5.0% respectively. The final equation was:Y=1.963-0.986× (CYP2C9* 3) +0.893× (VKORC1-1639) +0.002× (warfarin concentration)-0.019× (age). Conclusion Multiple regression equation including gene polymorphisms of CYP2C9 and VKORC1, non-genetic factors of coagulation factor activity, warfarin concentration, age, and body surface area can predict reasonable dosage of warfarin for anticoagulation to achieve individualized management of anticoagulation monitoring and reduce the anticoagulation complications.

Citation： WANGYu-qing, DONGLi, SHIYing-kang, HOUJiang-long, JIANGHong, FUBo. Correlation of Warfarin Dosage and Genetic Polymorphism of Han-patients after Heart Valve Replacement. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2016, 23(1): 1-6. doi: 10.7507/1007-4848.20160001 Copy

1.	Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogeno-mics and individualized drug therapy. Annu Rev Med, 2006, 57(6): 119-137.
2.	Kö rtke H, Kö rfer R. International normalized ratio self-management after mechanical heart valve replacement: is an early start advanta-geous? Ann Thorac Surg, 2001, 72(1): 44-48.
3.	Rieder MJ. Pharmacogenetics of warfarin treatment for potential clinical application. Current Cardiovascular Risk Reports, 2007, 1(5): 420-426.
4.	Bodin L, Verstuyft C, Tregouet DA, et al. Cytochrome P4502C9(CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood, 2005, 106(1): 135-140.
5.	Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood, 2005, 106(7): 2329-2333.
6.	Veenstra DL, You JHS, Rieder MJ, et al. Association of Vitamin K epoxide reductase complex 1(VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet genomics, 2005, 15(10): 687-691.
7.	Wieloch M, Sjä lander A, Frykman V, et al. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J, 2011, 32(18): 2282-2289.
8.	Kumar DK, Shewade DG, Loriot MA, et al. Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population. Eur J Clin Pharmacol, 2014, 70(1): 47-56.
9.	顾强, 陈柏成, 郝嘉, 等.重庆地区人工机械瓣膜置换术后患者VKORC1-1639A/G遗传基因多态性与华法林剂量调整的研究.第三军医大学学报, 2009, 31(23): 2370-2373.
10.	董力, 许建屏, 石应康.《瓣膜病术后抗凝个体化和低抗凝标准研究》阶段阶段研究进展.中国胸心血管外科临床杂志, 2013, 20(1): 1-2.
11.	Kamali F, Khan TI, King BP, et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther, 2004, 75(3): 204-212.
12.	Miao L, Yang J, Huang C, et al. Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients. Eur J Clin Pharmacol, 2007, 63(12): 1135-1141.
13.	Gurwitz JH, Avorn J, Ross-Degnan D, et al. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med, 1992, 116(11): 901-904.
14.	Loebstein R, Yonath H, Peleg D, et al. Interindividual variability in sensitivity to warfarin-Nature or nurture? Clin Pharmacol Ther, 2001, 70(2): 159-164.
15.	Lubetsky A, Dekel-Stern E, Chetrit A, et al. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost, 1999, 81: 396-399.
16.	侯江龙, 董力.基因多态性预测华法林维持剂量的研究进展.中国胸心血管外科临床杂志, 2015, 22(6): 585-590.
17.	Xie HG, Prasad HC, Kim RB, et al. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev, 2002, 54(10): 1257-1270.
18.	Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA, 2002, 287(13): 1690-1698.
19.	Yuan HY, Chen JJ, Lee MTM, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet, 2005, 14(13): 1745-1751.
20.	Yang L, Ge W, Yu F, et al. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement-A systematic review and meta-analysis. Thromb Res, 2010, 125(4): e159-e166.

1. Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogeno-mics and individualized drug therapy. Annu Rev Med, 2006, 57(6): 119-137.
2. Kö rtke H, Kö rfer R. International normalized ratio self-management after mechanical heart valve replacement: is an early start advanta-geous? Ann Thorac Surg, 2001, 72(1): 44-48.
3. Rieder MJ. Pharmacogenetics of warfarin treatment for potential clinical application. Current Cardiovascular Risk Reports, 2007, 1(5): 420-426.
4. Bodin L, Verstuyft C, Tregouet DA, et al. Cytochrome P4502C9(CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity. Blood, 2005, 106(1): 135-140.
5. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood, 2005, 106(7): 2329-2333.
6. Veenstra DL, You JHS, Rieder MJ, et al. Association of Vitamin K epoxide reductase complex 1(VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet genomics, 2005, 15(10): 687-691.
7. Wieloch M, Sjä lander A, Frykman V, et al. Anticoagulation control in Sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry AuriculA. Eur Heart J, 2011, 32(18): 2282-2289.
8. Kumar DK, Shewade DG, Loriot MA, et al. Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population. Eur J Clin Pharmacol, 2014, 70(1): 47-56.
9. 顾强, 陈柏成, 郝嘉, 等.重庆地区人工机械瓣膜置换术后患者VKORC1-1639A/G遗传基因多态性与华法林剂量调整的研究.第三军医大学学报, 2009, 31(23): 2370-2373.
10. 董力, 许建屏, 石应康.《瓣膜病术后抗凝个体化和低抗凝标准研究》阶段阶段研究进展.中国胸心血管外科临床杂志, 2013, 20(1): 1-2.
11. Kamali F, Khan TI, King BP, et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther, 2004, 75(3): 204-212.
12. Miao L, Yang J, Huang C, et al. Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients. Eur J Clin Pharmacol, 2007, 63(12): 1135-1141.
13. Gurwitz JH, Avorn J, Ross-Degnan D, et al. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med, 1992, 116(11): 901-904.
14. Loebstein R, Yonath H, Peleg D, et al. Interindividual variability in sensitivity to warfarin-Nature or nurture? Clin Pharmacol Ther, 2001, 70(2): 159-164.
15. Lubetsky A, Dekel-Stern E, Chetrit A, et al. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost, 1999, 81: 396-399.
16. 侯江龙, 董力.基因多态性预测华法林维持剂量的研究进展.中国胸心血管外科临床杂志, 2015, 22(6): 585-590.
17. Xie HG, Prasad HC, Kim RB, et al. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev, 2002, 54(10): 1257-1270.
18. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA, 2002, 287(13): 1690-1698.
19. Yuan HY, Chen JJ, Lee MTM, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet, 2005, 14(13): 1745-1751.
20. Yang L, Ge W, Yu F, et al. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement-A systematic review and meta-analysis. Thromb Res, 2010, 125(4): e159-e166.

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Correlation of Warfarin Dosage and Genetic Polymorphism of Han-patients after Heart Valve Replacement

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