Current research on the influence of genetic factors on warfarin maintenance dose_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZHANG Heng ,  DONG Li

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

Corresponding?author：

DONG Li, Email: donglikn199@163.com

Keywords：

Warfarin; gene polymorphisms; cytochrome P450 2C9; vitamin K epoxy reductase complex 1; γ-glutamine carboxylase; cytochrome P450 4F2; quinone oxidoreductase 1

DOI：

10.7507/1007-4848.201708038

Video：

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Warfarin is one of the most frequently prescribed oral anticoagulant. Many researches have shown that the genotypes have been strongly associated with warfarin maintenance doses. Especially, it has been accepted in academia that cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 subunit (VKORC1) could affect the warfarin maintenance doses. There are also many other genotypes that were reported to be related to warfarin doses, but the results have been in controversial so far. The studies found that the dose formula which contained the genetic factors and clinical information could accurately predict the maintenance dose of warfarin, however, its usefulness is suspected due to the inconsistent results of clinical trials. Large-sample and multi-center studies are necessary to verify the specific effects of gene and non-gene factors to warfarin dose; at the same time, testing constructed models or building new models help to improve the explained percentages of individual differences.

Citation： ZHANG Heng, DONG Li. Current research on the influence of genetic factors on warfarin maintenance dose. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2018, 25(8): 719-723. doi: 10.7507/1007-4848.201708038 Copy

1.	Lindh JD, Holm L, Dahl ML, et al. Incidence and predictors of severe bleeding during warfarin treatment. J Thromb Thrombolysis, 2008, 25(2): 151-159.
2.	Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133(6 Suppl): 160S-198S.
3.	Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thromb Res, 2007, 120(1): 1-10.
4.	Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev, 2006, 58(3): 521-590.
5.	Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol, 2004, 44(10): 1083-1105.
6.	Gage BF, Eby C, Milligan PE, et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost, 2004, 91(1): 87-94.
7.	Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J, 2007, 7(2): 99-111.
8.	Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med, 2005, 7(2): 97-104.
9.	Voora D, McLeod HL, Eby C, et al. The pharmacogenetics of coumarin therapy. Pharmacogenomics, 2005, 6(5): 503-513.
10.	D'Andrea G, D'Ambrosio R, Margaglione M. Oral anticoagulants: Pharmacogenetics relationship between genetic and non-genetic factors. Blood Rev, 2008, 22(3): 127-140.
11.	Wang D, Chen H, Momary KM, et al. Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood, 2008, 112(4): 1013-1021.
12.	Tian L, Zhang J, Xiao S, et al. Impact of polymorphisms of the GGCX gene on maintenance warfarin dose in Chinese populations: Systematic review and meta-analysis. Meta Gene, 2015, 5: 43-54.
13.	Rieder MJ, Reiner AP, Rettie AE. Gamma-glutamyl carboxylase (GGCX) tagSNPs have limited utility for predicting warfarin maintenance dose. J Thromb Haemost, 2007, 5(11): 2227-2234.
14.	Sun Y, Wu Z, Li S, et al. Impact of gamma-glutamyl carboxylase gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis. Thromb Res, 2015, 135(4): 739-747.
15.	Gong X, Gutala R, Jaiswal AK. Quinone oxidoreductases and vitamin K metabolism. Vitam Horm, 2008, 78: 85-101.
16.	Traver RD, Siegel D, Beall HD, et al. Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase). Br J Cancer, 1997, 75(1): 69-75.
17.	Kelsey KT, Ross D, Traver RD, et al. Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy. Br J Cancer, 1997, 76(7): 852-854.
18.	de Visser MC, Roshani S, Rutten JW, et al. 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, 2011, 106(3): 563-565.
19.	Hirai K, Hayashi H, Ono Y, et al. Influence of CYP4F2 polymorphisms and plasma vitamin K levels on warfarin sensitivity in Japanese pediatric patients. Drug Metab Pharmacokinet, 2013, 28(2): 132-137.
20.	Singh O, Sandanaraj E, Subramanian K, et al. Influence of CYP4F2 rs2108622 (V433M) on warfarin dose requirement in Asian patients. Drug Metab Pharmacokinet, 2011, 26(2): 130-136.
21.	Hirai K, Yamada Y, Hayashi H, et al. Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy. Thromb Res, 2015, 135(5): 861-866.
22.	Liang R, Wang C, Zhao H, et al. Influence of CYP4F2 genotype on warfarin dose requirement-a systematic review and meta-analysis. Thromb Res, 2012, 130(1): 38-44.
23.	Gan GG, Phipps ME, Lee MM, et al. Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations. Ann Hematol, 2011, 90(6): 635-641.
24.	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.
25.	Lindh JD, Holm L, Andersson ML, et al. Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis. Eur J Clin Pharmacol, 2009, 65(4): 365-375.
26.	Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J, 2003, 3(4): 202-214.
27.	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.
28.	Liang R, Li L, Li C, et al. Impact of CYP2C9*3, VKORC1-1639, CYP4F2rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients. J Thromb Thrombolysis, 2012, 34(1): 120-125.
29.	Sun X, Yu WY, Ma WL, et al. Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose: A systematic review and meta-analysis. Biomed Rep, 2016, 4(4): 498-506.
30.	Sun Y, Wu Z, Li S, et al. Impact of gamma-glutamyl carboxylase gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis. Thromb Res, 2015, 135(4): 739-747.
31.	Liu YQ, Yang BH, Xia JM, et al. Research on correlation between GGCX (rs6738645) polymorphism and warfarin stable dose. Chongqing Med, 2014, 43(10): 1184-1186.
32.	Huang SW, Xiang DK, Huang L, et al. Influence of GGCX genotype on warfarin dose requirements in Chinese patients. Thromb Res, 2011, 127(2): 131-134.
33.	Kamali X, Wulasihan M, Yang YC, et al. Association of GGCX gene polymorphism with warfarin dose in atrial fibrillation population in Xinjiang. Lipids Health Dis, 2013, 12: 149.
34.	Dang MT, Hambleton J, Kayser SR. The influence of ethnicity on warfarin dosage requirement. Ann Pharmacother, 2005, 39(6): 1008-1012.
35.	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.
36.	Perera MA, Cavallari LH, Limdi NA, et al. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet, 2013, 382(9894): 790-796.
37.	Fung E, Patsopoulos NA, Belknap SM, et al. Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. Semin Thromb Hemost, 2012, 38(8): 893-904.
38.	Su W, Mrug S, Windle M. Social cognitive and emotional mediators link violence exposure and parental nurturance to adolescent aggression. J Clin Child Adolesc Psychol, 2010, 39(6): 814-824.
39.	侯江龍, 董鑫, 王玉慶, 等. 非遺傳因素與基因多態性對華法林臨床用藥穩定維持劑量的影響. 中國醫學遺傳學雜志, 2015, 32(5): 629-634.
40.	Garcia D, Regan S, Crowther M, et al. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest, 2005, 127(6): 2049-2056.
41.	Harada T, Ariyoshi N, Shimura H, et al. Application of Akaike information criterion to evaluate warfarin dosing algorithm. Thromb Res, 2010, 126(3): 183-190.
42.	王玉慶, 董力, 石應康, 等. 漢族人心臟瓣膜置換術后華法林用藥劑量與基因型關系的相關性研究. 中國胸心血管外科臨床雜志, 2016, 23(1): 1-6.
43.	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.
44.	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.
45.	Cavallari LH, Nutescu EA. Warfarin pharmacogenetics: to genotype or not to genotype, that is the question. Clin Pharmacol Ther, 2014, 96(1): 22-24.

1. Lindh JD, Holm L, Dahl ML, et al. Incidence and predictors of severe bleeding during warfarin treatment. J Thromb Thrombolysis, 2008, 25(2): 151-159.
2. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest, 2008, 133(6 Suppl): 160S-198S.
3. Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thromb Res, 2007, 120(1): 1-10.
4. Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev, 2006, 58(3): 521-590.
5. Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol, 2004, 44(10): 1083-1105.
6. Gage BF, Eby C, Milligan PE, et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost, 2004, 91(1): 87-94.
7. Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J, 2007, 7(2): 99-111.
8. Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med, 2005, 7(2): 97-104.
9. Voora D, McLeod HL, Eby C, et al. The pharmacogenetics of coumarin therapy. Pharmacogenomics, 2005, 6(5): 503-513.
10. D'Andrea G, D'Ambrosio R, Margaglione M. Oral anticoagulants: Pharmacogenetics relationship between genetic and non-genetic factors. Blood Rev, 2008, 22(3): 127-140.
11. Wang D, Chen H, Momary KM, et al. Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood, 2008, 112(4): 1013-1021.
12. Tian L, Zhang J, Xiao S, et al. Impact of polymorphisms of the GGCX gene on maintenance warfarin dose in Chinese populations: Systematic review and meta-analysis. Meta Gene, 2015, 5: 43-54.
13. Rieder MJ, Reiner AP, Rettie AE. Gamma-glutamyl carboxylase (GGCX) tagSNPs have limited utility for predicting warfarin maintenance dose. J Thromb Haemost, 2007, 5(11): 2227-2234.
14. Sun Y, Wu Z, Li S, et al. Impact of gamma-glutamyl carboxylase gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis. Thromb Res, 2015, 135(4): 739-747.
15. Gong X, Gutala R, Jaiswal AK. Quinone oxidoreductases and vitamin K metabolism. Vitam Horm, 2008, 78: 85-101.
16. Traver RD, Siegel D, Beall HD, et al. Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase). Br J Cancer, 1997, 75(1): 69-75.
17. Kelsey KT, Ross D, Traver RD, et al. Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy. Br J Cancer, 1997, 76(7): 852-854.
18. de Visser MC, Roshani S, Rutten JW, et al. 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, 2011, 106(3): 563-565.
19. Hirai K, Hayashi H, Ono Y, et al. Influence of CYP4F2 polymorphisms and plasma vitamin K levels on warfarin sensitivity in Japanese pediatric patients. Drug Metab Pharmacokinet, 2013, 28(2): 132-137.
20. Singh O, Sandanaraj E, Subramanian K, et al. Influence of CYP4F2 rs2108622 (V433M) on warfarin dose requirement in Asian patients. Drug Metab Pharmacokinet, 2011, 26(2): 130-136.
21. Hirai K, Yamada Y, Hayashi H, et al. Plasma vitamin K concentrations depend on CYP4F2 polymorphism and influence on anticoagulation in Japanese patients with warfarin therapy. Thromb Res, 2015, 135(5): 861-866.
22. Liang R, Wang C, Zhao H, et al. Influence of CYP4F2 genotype on warfarin dose requirement-a systematic review and meta-analysis. Thromb Res, 2012, 130(1): 38-44.
23. Gan GG, Phipps ME, Lee MM, et al. Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations. Ann Hematol, 2011, 90(6): 635-641.
24. 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.
25. Lindh JD, Holm L, Andersson ML, et al. Influence of CYP2C9 genotype on warfarin dose requirements--a systematic review and meta-analysis. Eur J Clin Pharmacol, 2009, 65(4): 365-375.
26. Takahashi H, Echizen H. Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Pharmacogenomics J, 2003, 3(4): 202-214.
27. 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.
28. Liang R, Li L, Li C, et al. Impact of CYP2C9*3, VKORC1-1639, CYP4F2rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients. J Thromb Thrombolysis, 2012, 34(1): 120-125.
29. Sun X, Yu WY, Ma WL, et al. Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose: A systematic review and meta-analysis. Biomed Rep, 2016, 4(4): 498-506.
30. Sun Y, Wu Z, Li S, et al. Impact of gamma-glutamyl carboxylase gene polymorphisms on warfarin dose requirement: a systematic review and meta-analysis. Thromb Res, 2015, 135(4): 739-747.
31. Liu YQ, Yang BH, Xia JM, et al. Research on correlation between GGCX (rs6738645) polymorphism and warfarin stable dose. Chongqing Med, 2014, 43(10): 1184-1186.
32. Huang SW, Xiang DK, Huang L, et al. Influence of GGCX genotype on warfarin dose requirements in Chinese patients. Thromb Res, 2011, 127(2): 131-134.
33. Kamali X, Wulasihan M, Yang YC, et al. Association of GGCX gene polymorphism with warfarin dose in atrial fibrillation population in Xinjiang. Lipids Health Dis, 2013, 12: 149.
34. Dang MT, Hambleton J, Kayser SR. The influence of ethnicity on warfarin dosage requirement. Ann Pharmacother, 2005, 39(6): 1008-1012.
35. 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.
36. Perera MA, Cavallari LH, Limdi NA, et al. Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. Lancet, 2013, 382(9894): 790-796.
37. Fung E, Patsopoulos NA, Belknap SM, et al. Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. Semin Thromb Hemost, 2012, 38(8): 893-904.
38. Su W, Mrug S, Windle M. Social cognitive and emotional mediators link violence exposure and parental nurturance to adolescent aggression. J Clin Child Adolesc Psychol, 2010, 39(6): 814-824.
39. 侯江龍, 董鑫, 王玉慶, 等. 非遺傳因素與基因多態性對華法林臨床用藥穩定維持劑量的影響. 中國醫學遺傳學雜志, 2015, 32(5): 629-634.
40. Garcia D, Regan S, Crowther M, et al. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population. Chest, 2005, 127(6): 2049-2056.
41. Harada T, Ariyoshi N, Shimura H, et al. Application of Akaike information criterion to evaluate warfarin dosing algorithm. Thromb Res, 2010, 126(3): 183-190.
42. 王玉慶, 董力, 石應康, 等. 漢族人心臟瓣膜置換術后華法林用藥劑量與基因型關系的相關性研究. 中國胸心血管外科臨床雜志, 2016, 23(1): 1-6.
43. 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.
44. 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.
45. Cavallari LH, Nutescu EA. Warfarin pharmacogenetics: to genotype or not to genotype, that is the question. Clin Pharmacol Ther, 2014, 96(1): 22-24.

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