Research Progress in the Effects of Gene Polymorphisms on Warfarin Maintenance Doses_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

HouJiang-long ,  DongLi

Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

DongLi, Email: donglikn199@163.com

Keywords：

Warfarin; Gene polymorphisms; Maintenance doses; Cytochrome P450 2C9(CYP2C9); Vitamin K epoxide reductase complex 1(VKORC1)

DOI：

10.7507/1007-4848.20150148

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Warfarin is one of the most frequently prescribed oral anticoagulant. Many researches have shown that the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) genotypes have been strongly associated with warfarin maintenance doses. Warfarin maintenance doses can be accurately predicted by use of dosing algorithms including genetic and clinical information. Although several clinical trials demonstrated mixed results, calling into question the utility of this approach. The present data do not support genetic testing to guide warfarin maintenance doses, but in the setting where genotype data are available, use of this approach is reasonable. Ongoing trials are expected to provide more data, and more work is needed to define dosing algorithms that include appropriate variables in minority populations. All these work will further improve the clinical application of genotype-guided warfarin maintenance doses.

Citation： HouJiang-long, DongLi. Research Progress in the Effects of Gene Polymorphisms on Warfarin Maintenance Doses. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2015, 22(6): 585-590. doi: 10.7507/1007-4848.20150148 Copy

1.	Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treat-ment of acute venous thromboembolism. N Engl J Med, 2013, 369 (9): 799-808.
2.	Kirley K, Qato DM, Kornfield R, et al. National trends in oral anti-coagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes, 2012, 5(5): 615-621.
3.	Budnitz DS, Lovegrove MC, Shehab N, et al. Emergency hospitaliza-tions for adverse drug events in older Americans. N Engl J Med, 2011, 365(21): 2002-2012.
4.	Limdi NA, McGwin G, Goldstein JA, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic comp-lications in African-American and European-American patients on warfarin. Clin Pharmacol Ther, 2008, 83(2): 312-321.
5.	张亚同, 梁欣, 董凡, 等. 中国人群CYP4F2基因多态性对华法林抗凝作用的影响. 临床药物治疗杂志, 2014, 12(1): 41-45.
6.	Limdi NA, Wadelius M, Cavallari L, et al. Warfarin pharmacogene-tics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood, 2010, 115(18): 3827-3834.
7.	闻武, 黄烽, 阳丽梅, 等. CYP2C93, VKORC1-1639G>A和CYP4F2 rs2108622基因多态性对华法林剂量的影响. 中国胸心血管外科临床杂志, 2013, 20(4): 375-380.
8.	Bress A, Patel SR, Perera MA, et al. Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans. Pharmacogenomics, 2012, 13(16): 1925-1935.
9.	Perera MA, Cavallari LH, Limdi NA, et al. Genetic variants associa-ted with warfarin dose in African-American individuals: a genome-wide association study. Lancet, 2013, 382(9894): 790-796.
10.	Cha PC, Mushiroda T, Takahashi A, et al. Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Hum Mol Genet, 2010, 19(23): 4735-4744.
11.	NⅡnuma Y, Saito T, Takahashi M, et al. Functional characterization of 32 CYP2C9 allelic variants. Pharmacogenomics J, 2014, 14(2): 107-114.
12.	鲁晓春, 李世英. 中国人VKORC1基因多态性对华法林维持剂量影响的Meta分析. 心肺血管病杂志, 2012, 31(3): 259-263.
13.	Caldwell MD, Awad T, Johnson JA, et al. CYP4F2 genetic variant alters required warfarin dose. Blood, 2008, 111(8): 4106-4112.
14.	McDonald MG, Rieder MJ, Nakano M, et al. CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol, 2009, 75(6): 1337-1346.
15.	Jorgensen AL, FitzGerald RJ, Oyee J, et al. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. Plos One, 2012, 7(8): e44064.
16.	Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood, 2009, 113(4): 784-792.
17.	Cooper GM, Johnson JA, Langaee TY, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood, 2008, 112(4): 1022-1027.
18.	Takeuchi F, McGinnis R, Bourgeois S, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet, 2009, 5(3): e1000433.
19.	Yang J, Chen Y, Li X, et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol, 2013, 168(4): 4234-4243.
20.	Finkelman BS, Gage BF, Johnson JA, et al. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol, 2011, 57(5): 612-618.
21.	王永, 许金国, 万镇, 等. 综合CYP2C9、VKORC1基因型和INR值建立华法林个体化剂量公式. 临床合理用药杂志, 2014, 7(1): 112-113.
22.	Anderson JL, Horne BD, Stevens SM, et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-Ⅱ). Circulation, 2012, 125(16): 1997-2005.
23.	Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med, 2013, 369(24): 2283-2293.
24.	Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med, 2013, 369(24): 2294-2303.
25.	Avery PJ, Jorgensen A, Hamberg AK, et al. A proposal for an indivi-dualized pharmacogenetics-based warfarin initiation dos regimen for patients commencing anticoagulation therapy. Clin Pharmacol Ther, 2011, 90(5): 701-706.
26.	Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther, 2008, 84(3): 326-331.
27.	Verhoef TI, Redekop WK, Daly AK, et al. Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon. Br J Clin Pharmacol, 2014, 77(4): 626-641.
28.	Cavallari LH, Langaee TY, Momary KM, et al. Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther, 2010, 87(4): 459-464.
29.	Holbrook A, Schulman S, Witt DM, et al. Evidence-based manage-ment of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012, 141(2 Suppl): e152S-e184S.
30.	Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical pharmacogene-tics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther, 2011, 90(4): 625-629.
31.	Stergiopoulos K, Brown DL. Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA Intern Med, 2014, 174(8): 1330-1338.
32.	Liao Z, Feng S, Ling P, et al. Meta-analysis of randomized controlled trials reveals an improved clinical outcome of using genotype plus clinical algorithm for warfarin dosing. J Thromb Thrombolysis, 2015, 39(2): 228-234.
33.	Hernandez W, Gamazon ER, Aquino-Michaels K, et al. Ethnicity-specific pharmacogenetics: the case of warfarin in African Ameri-cans. Pharmacogenomics J, 2014, 14(3): 223-228.

1. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treat-ment of acute venous thromboembolism. N Engl J Med, 2013, 369 (9): 799-808.
2. Kirley K, Qato DM, Kornfield R, et al. National trends in oral anti-coagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes, 2012, 5(5): 615-621.
3. Budnitz DS, Lovegrove MC, Shehab N, et al. Emergency hospitaliza-tions for adverse drug events in older Americans. N Engl J Med, 2011, 365(21): 2002-2012.
4. Limdi NA, McGwin G, Goldstein JA, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic comp-lications in African-American and European-American patients on warfarin. Clin Pharmacol Ther, 2008, 83(2): 312-321.
5. 张亚同, 梁欣, 董凡, 等. 中国人群CYP4F2基因多态性对华法林抗凝作用的影响. 临床药物治疗杂志, 2014, 12(1): 41-45.
6. Limdi NA, Wadelius M, Cavallari L, et al. Warfarin pharmacogene-tics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood, 2010, 115(18): 3827-3834.
7. 闻武, 黄烽, 阳丽梅, 等. CYP2C93, VKORC1-1639G>A和CYP4F2 rs2108622基因多态性对华法林剂量的影响. 中国胸心血管外科临床杂志, 2013, 20(4): 375-380.
8. Bress A, Patel SR, Perera MA, et al. Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans. Pharmacogenomics, 2012, 13(16): 1925-1935.
9. Perera MA, Cavallari LH, Limdi NA, et al. Genetic variants associa-ted with warfarin dose in African-American individuals: a genome-wide association study. Lancet, 2013, 382(9894): 790-796.
10. Cha PC, Mushiroda T, Takahashi A, et al. Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Hum Mol Genet, 2010, 19(23): 4735-4744.
11. NⅡnuma Y, Saito T, Takahashi M, et al. Functional characterization of 32 CYP2C9 allelic variants. Pharmacogenomics J, 2014, 14(2): 107-114.
12. 鲁晓春, 李世英. 中国人VKORC1基因多态性对华法林维持剂量影响的Meta分析. 心肺血管病杂志, 2012, 31(3): 259-263.
13. Caldwell MD, Awad T, Johnson JA, et al. CYP4F2 genetic variant alters required warfarin dose. Blood, 2008, 111(8): 4106-4112.
14. McDonald MG, Rieder MJ, Nakano M, et al. CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol, 2009, 75(6): 1337-1346.
15. Jorgensen AL, FitzGerald RJ, Oyee J, et al. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. Plos One, 2012, 7(8): e44064.
16. Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood, 2009, 113(4): 784-792.
17. Cooper GM, Johnson JA, Langaee TY, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood, 2008, 112(4): 1022-1027.
18. Takeuchi F, McGinnis R, Bourgeois S, et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet, 2009, 5(3): e1000433.
19. Yang J, Chen Y, Li X, et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol, 2013, 168(4): 4234-4243.
20. Finkelman BS, Gage BF, Johnson JA, et al. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol, 2011, 57(5): 612-618.
21. 王永, 许金国, 万镇, 等. 综合CYP2C9、VKORC1基因型和INR值建立华法林个体化剂量公式. 临床合理用药杂志, 2014, 7(1): 112-113.
22. Anderson JL, Horne BD, Stevens SM, et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-Ⅱ). Circulation, 2012, 125(16): 1997-2005.
23. Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med, 2013, 369(24): 2283-2293.
24. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med, 2013, 369(24): 2294-2303.
25. Avery PJ, Jorgensen A, Hamberg AK, et al. A proposal for an indivi-dualized pharmacogenetics-based warfarin initiation dos regimen for patients commencing anticoagulation therapy. Clin Pharmacol Ther, 2011, 90(5): 701-706.
26. Gage BF, Eby C, Johnson JA, et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther, 2008, 84(3): 326-331.
27. Verhoef TI, Redekop WK, Daly AK, et al. Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon. Br J Clin Pharmacol, 2014, 77(4): 626-641.
28. Cavallari LH, Langaee TY, Momary KM, et al. Genetic and clinical predictors of warfarin dose requirements in African Americans. Clin Pharmacol Ther, 2010, 87(4): 459-464.
29. Holbrook A, Schulman S, Witt DM, et al. Evidence-based manage-ment of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012, 141(2 Suppl): e152S-e184S.
30. Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical pharmacogene-tics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther, 2011, 90(4): 625-629.
31. Stergiopoulos K, Brown DL. Genotype-guided vs clinical dosing of warfarin and its analogues: meta-analysis of randomized clinical trials. JAMA Intern Med, 2014, 174(8): 1330-1338.
32. Liao Z, Feng S, Ling P, et al. Meta-analysis of randomized controlled trials reveals an improved clinical outcome of using genotype plus clinical algorithm for warfarin dosing. J Thromb Thrombolysis, 2015, 39(2): 228-234.
33. Hernandez W, Gamazon ER, Aquino-Michaels K, et al. Ethnicity-specific pharmacogenetics: the case of warfarin in African Ameri-cans. Pharmacogenomics J, 2014, 14(3): 223-228.

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