Influence of CYP2C9 *3, VKORC1-1639 G>A and CYP4F2 rs2108622 Genetic Polymorphisms on Warfarin Dosage_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WEN Wu , HUANG Feng , YANG Limei , HAN Tao.

1. Provincial Clinical Medical College of Fujian Medical University，Fuzhou，350001，P. R. China;;
2. Department of Cardiovascular Surgery，Fujian Provincial Hospital，Fujian Provincial Institute of Cardiovascular Disease, Provincial Clinical Medical College of Fujian Medical University，Fuzhou，350001，P.R.China;;
3. Department of Pharmacy，Fujian Provincial Hospital，Provincial Clinical Medical College of Fujian Medical University，Fuzhou，350001，P. R. China;

Corresponding author：

Keywords：

CYP2C9 *3; 　VKORC1-1639 G＞A; 　CYP4F2 rs2108622; 　Genetic polymorphism; 　Warfarin

DOI：

10.7507/1007-4848.20130121

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Objective To investigate the influence of CYP2C9 3，VKORC1-1639 G＞A and CYP4F2 rs2108622 genetic polymorphisms on warfarin dosages of patients after heart valve replacement. Methods A total of 133 patients　undergoing heart valve replacement in the Department of Cardiovascular Surgery of Fujian Provincial Hospital from November　2011 to August 2012 were included in this study. Polymerase chain reaction（PCR）gene sequencing was performed to detect CYP2C9 3，VKORC1-1639 G＞A and CYP4F2 rs2108622 genetic polymorphism of these 133 patients. Patients were grouped according to their genotypes，and average warfarin dosages were compared between different genotype groups. Results The frequencies of CYP2C9 3 AA，AC and CC were 127 patients，6 patients and 0 patient respectively，and average daily warfarin dosages were 3.75 mg and 2.13 mg respectively which were statistically different between differentCYP2C9 3 genotypes （P＜0.05）. The frequencies of VKORC1-1639 G＞A GG，GA and AA were 3 patients，32 patientsand 98 patients respectively，and average daily warfarin dosages were 6.00 mg，4.50 mg and 3.00 mg respectively which were statistically different between different VKORC1-1639 G＞A genotypes （P＜0.05）. The frequencies of CYP4F2 rs 2108622 CC，CT and TT were 67 patients，59 patients and 7 patients respectively，and average daily warfarin dosages were 3.00 mg，3.75 mg and 4.50 mg respectively which were statistically different between different CYP4F2 rs2108622 genotypes（P＜0.05）. Conclusion CYP2C9 3，VKORC1-1639 G＞A and CYP4F2 rs2108622 genetic polymorphisms are　associated with individual difference of warfarin dosages of patients after heart valve replacement.

Citation： WEN Wu,HUANG Feng,YANG Limei,HAN Tao.. Influence of CYP2C9 *3, VKORC1-1639 G>A and CYP4F2 rs2108622 Genetic Polymorphisms on Warfarin Dosage. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2013, 20(4): 375-380. doi: 10.7507/1007-4848.20130121 Copy

1. 　Scott SA， Patel M， Martis S， et al. Copy number variation and warfarin dosing：evaluation of CYP2C9， VKORC1， CYP4F2， GGCX and CALU. Pharmacogenomics， 2012， 13 （3）：297-307.

2. 　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.

3. 　Caldwell MD， Berg RL， Zhang KQ， et al. Evaluation of genetic　factors for warfarin dose prediction. Clin Med Res， 2007， 5 （1）：8-16.

4. 　Suh DC， Nelson WW， Choi JC， et al. Risk of hemorrhage and treatment costs associated with warfarin drug interactions in patients with atrial fibrillation. Clin Ther， 2012， 34 （7）：1569-1582.

5. 　Hines LE， Ceron-Cabrera D， Romero K， et al. Evaluation of warfarin　drug interaction listings in US product information for warfarin and interacting drugs. Clin Ther， 2011， 33 （1）：36-45.

6. 　Holbrook AM， Pereira JA， Labiris R， et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med， 2005， 165 （10）：1095-1106.

7. 　Wittkowsky AK. A systematic review and inventory of supplement effects on warfarin and other anticoagulants. Thromb Res， 2005， 117 （1-2）：81-86.

8. 　Schelleman H， Chen Z， Kealey C， et al. Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther， 2007， 81 （5）：742-747.

9. 　Yuan HY， Chen JJ， Lee MT， 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.

10. 　Caldwell MD， Awad T， Johnson JA， et al. CYP4F2 genetic variant alters required warfarin dose. Blood， 2008， 111 （8）：4106-4112.

11. 　Nakamura K， Obayashi K， Araki T， et al. CYP4F2 gene polymorphism as a contributor to warfarin maintenance dose in Japanese subj-ects. J Clin Pharm Ther， 2012， 37 （4）：481-485.

12. 　Cen HJ， Zeng WT， Leng XY， et al. CYP4F2 rs2108622：a minor　significant genetic factor of warfarin dose in Han Chinese patients with mechanical heart valve replacement. Br J Clin Pharmacol， 2010，70 （2）：234-240.

13. 　Zeng WT， Zheng QS， Huang M， et al. Genetic polymorphisms of VKORC1， CYP2C9， CYP4F2 in Bai， Tibetan Chinese. Pharmazie， 2012， 67 （1）：69-73.

14. 　dbSNP Short Genetic Variations. [2012-10-12]. http：//www. ncbi. nlm. nih.gov.

15. 　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.

16. 　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.

17. 　Suriapranata IM， Tjong WY， Wang T， et al. Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians . BMC Med Genet， 2011， 12：80.

18. 　International Warfarin Pharmacogenetics Consortium， Klein TE， Altman RB， et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med， 2009， 360 （8）：753-764.

19. 　Zhang JE， Jorgensen AL， Alfirevic A， et al. Effects of CYP4F2　genetic polymorphisms and haplotypes on clinical outcomes in patientsinitiated on warfarin therapy. Pharmacogenet Genomics， 2009， 19 （10）：781-789.

20. 　Pathare AV， Al Zadjali S， Misquith R， et al. Warfarin pharmacogenetics：polymorphisms of the CYP2C9， CYP4F2， and VKORC1 loci in a genetically admixed Omani population. Hum Biol， 2012， 84 （1）：67-77.

21. 　Borgiani P， Ciccacci C， Forte V， et al. CYP4F2 genetic variant （rs2108622） significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics， 2009， 10 （2）：261-266.

22. 　Kringen MK， Haug KB， Grimholt RM， et al. Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction. J Biomed Biotechnol， 2011，2011：739751.

1. 　Scott SA， Patel M， Martis S， et al. Copy number variation and warfarin dosing：evaluation of CYP2C9， VKORC1， CYP4F2， GGCX and CALU. Pharmacogenomics， 2012， 13 （3）：297-307.

2. 　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.

3. 　Caldwell MD， Berg RL， Zhang KQ， et al. Evaluation of genetic　factors for warfarin dose prediction. Clin Med Res， 2007， 5 （1）：8-16.

4. 　Suh DC， Nelson WW， Choi JC， et al. Risk of hemorrhage and treatment costs associated with warfarin drug interactions in patients with atrial fibrillation. Clin Ther， 2012， 34 （7）：1569-1582.

5. 　Hines LE， Ceron-Cabrera D， Romero K， et al. Evaluation of warfarin　drug interaction listings in US product information for warfarin and interacting drugs. Clin Ther， 2011， 33 （1）：36-45.

6. 　Holbrook AM， Pereira JA， Labiris R， et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med， 2005， 165 （10）：1095-1106.

7. 　Wittkowsky AK. A systematic review and inventory of supplement effects on warfarin and other anticoagulants. Thromb Res， 2005， 117 （1-2）：81-86.

8. 　Schelleman H， Chen Z， Kealey C， et al. Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther， 2007， 81 （5）：742-747.

9. 　Yuan HY， Chen JJ， Lee MT， 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.

10. 　Caldwell MD， Awad T， Johnson JA， et al. CYP4F2 genetic variant alters required warfarin dose. Blood， 2008， 111 （8）：4106-4112.

11. 　Nakamura K， Obayashi K， Araki T， et al. CYP4F2 gene polymorphism as a contributor to warfarin maintenance dose in Japanese subj-ects. J Clin Pharm Ther， 2012， 37 （4）：481-485.

12. 　Cen HJ， Zeng WT， Leng XY， et al. CYP4F2 rs2108622：a minor　significant genetic factor of warfarin dose in Han Chinese patients with mechanical heart valve replacement. Br J Clin Pharmacol， 2010，70 （2）：234-240.

13. 　Zeng WT， Zheng QS， Huang M， et al. Genetic polymorphisms of VKORC1， CYP2C9， CYP4F2 in Bai， Tibetan Chinese. Pharmazie， 2012， 67 （1）：69-73.

14. 　dbSNP Short Genetic Variations. [2012-10-12]. http：//www. ncbi. nlm. nih.gov.

15. 　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.

16. 　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.

17. 　Suriapranata IM， Tjong WY， Wang T， et al. Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians . BMC Med Genet， 2011， 12：80.

18. 　International Warfarin Pharmacogenetics Consortium， Klein TE， Altman RB， et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med， 2009， 360 （8）：753-764.

19. 　Zhang JE， Jorgensen AL， Alfirevic A， et al. Effects of CYP4F2　genetic polymorphisms and haplotypes on clinical outcomes in patientsinitiated on warfarin therapy. Pharmacogenet Genomics， 2009， 19 （10）：781-789.

20. 　Pathare AV， Al Zadjali S， Misquith R， et al. Warfarin pharmacogenetics：polymorphisms of the CYP2C9， CYP4F2， and VKORC1 loci in a genetically admixed Omani population. Hum Biol， 2012， 84 （1）：67-77.

21. 　Borgiani P， Ciccacci C， Forte V， et al. CYP4F2 genetic variant （rs2108622） significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics， 2009， 10 （2）：261-266.

22. 　Kringen MK， Haug KB， Grimholt RM， et al. Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction. J Biomed Biotechnol， 2011，2011：739751.

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Influence of CYP2C9 *3, VKORC1-1639 G>A and CYP4F2 rs2108622 Genetic Polymorphisms on Warfarin Dosage

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1.	Scott SA， Patel M， Martis S， et al. Copy number variation and warfarin dosing：evaluation of CYP2C9， VKORC1， CYP4F2， GGCX and CALU. Pharmacogenomics， 2012， 13 （3）：297-307.
2.	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.
3.	Caldwell MD， Berg RL， Zhang KQ， et al. Evaluation of genetic　factors for warfarin dose prediction. Clin Med Res， 2007， 5 （1）：8-16.
4.	Suh DC， Nelson WW， Choi JC， et al. Risk of hemorrhage and treatment costs associated with warfarin drug interactions in patients with atrial fibrillation. Clin Ther， 2012， 34 （7）：1569-1582.
5.	Hines LE， Ceron-Cabrera D， Romero K， et al. Evaluation of warfarin　drug interaction listings in US product information for warfarin and interacting drugs. Clin Ther， 2011， 33 （1）：36-45.
6.	Holbrook AM， Pereira JA， Labiris R， et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med， 2005， 165 （10）：1095-1106.
7.	Wittkowsky AK. A systematic review and inventory of supplement effects on warfarin and other anticoagulants. Thromb Res， 2005， 117 （1-2）：81-86.
8.	Schelleman H， Chen Z， Kealey C， et al. Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther， 2007， 81 （5）：742-747.
9.	Yuan HY， Chen JJ， Lee MT， 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.
10.	Caldwell MD， Awad T， Johnson JA， et al. CYP4F2 genetic variant alters required warfarin dose. Blood， 2008， 111 （8）：4106-4112.
11.	Nakamura K， Obayashi K， Araki T， et al. CYP4F2 gene polymorphism as a contributor to warfarin maintenance dose in Japanese subj-ects. J Clin Pharm Ther， 2012， 37 （4）：481-485.
12.	Cen HJ， Zeng WT， Leng XY， et al. CYP4F2 rs2108622：a minor　significant genetic factor of warfarin dose in Han Chinese patients with mechanical heart valve replacement. Br J Clin Pharmacol， 2010，70 （2）：234-240.
13.	Zeng WT， Zheng QS， Huang M， et al. Genetic polymorphisms of VKORC1， CYP2C9， CYP4F2 in Bai， Tibetan Chinese. Pharmazie， 2012， 67 （1）：69-73.
14.	dbSNP Short Genetic Variations. [2012-10-12]. http：//www. ncbi. nlm. nih.gov.
15.	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.
16.	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.
17.	Suriapranata IM， Tjong WY， Wang T， et al. Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians . BMC Med Genet， 2011， 12：80.
18.	International Warfarin Pharmacogenetics Consortium， Klein TE， Altman RB， et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med， 2009， 360 （8）：753-764.
19.	Zhang JE， Jorgensen AL， Alfirevic A， et al. Effects of CYP4F2　genetic polymorphisms and haplotypes on clinical outcomes in patientsinitiated on warfarin therapy. Pharmacogenet Genomics， 2009， 19 （10）：781-789.
20.	Pathare AV， Al Zadjali S， Misquith R， et al. Warfarin pharmacogenetics：polymorphisms of the CYP2C9， CYP4F2， and VKORC1 loci in a genetically admixed Omani population. Hum Biol， 2012， 84 （1）：67-77.
21.	Borgiani P， Ciccacci C， Forte V， et al. CYP4F2 genetic variant （rs2108622） significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics， 2009， 10 （2）：261-266.
22.	Kringen MK， Haug KB， Grimholt RM， et al. Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction. J Biomed Biotechnol， 2011，2011：739751.