Drug/Small Molecule:

warfarin

Overview

Generic Names:	Warfarin sodium
IUPAC Name:	2-hydroxy-3-(3-oxo-1-phenylbutyl)chromen-4-one
Trade Names:	Athrombin; Athrombin-K; Athrombine-K; Brumolin; Co-Rax; Coumadin; Coumafen; Coumafene; Coumaphen; Coumaphene; Coumarins; Coumefene; D-Con; Dethmor; Dethnel; Dicusat E; Frass-Ratron; Jantoven; Kumader; Kumadu; Kumatox; Kypfarin; Latka 42; Mar-Frin; Marevan; Maveran; Panwarfin; Place-Pax; Prothromadin; RAX; Rosex; Sofarin; Solfarin; Sorexa Plus; Temus W; Tintorane; Tox-Hid; Vampirinip II; Vampirinip III; Waran; Warf 42; Warfarat; Warfarin Plus; Warfarin Q; Warfarine; Warficide; Warfilone; Zoocoumarin
PharmGKB Accession Id:	PA451906

Description

An anticoagulant that acts by inhibiting the synthesis of vitamin K-dependent coagulation factors. Warfarin is indicated for the prophylaxis and/or treatment of venous thrombosis and its extension, pulmonary embolism, and atrial fibrillation with embolization. It is also used as an adjunct in the prophylaxis of systemic embolism after myocardial infarction. Warfarin is also used as a rodenticide. [PubChem]

Indication

For the treatment of retinal vascular occlusion, pulmonary embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral embolism, transient cerebral ischaemia, arterial embolism and thrombosis.

ATC Therapeutic Category

• B01AA:Vitamin K antagonists

Pharmacology and Interactions

Mechanism Of Action

Warfarin inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decresed prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.

Pharmacology

Warfarin, a coumarin anticoagulant, is a racemic mixture of two active isomers. It is used in the prevention and treatment of thromboembolic disease including venous thrombosis, thromboembolism, and pulmonary embolism as well as for the prevention of ischemic stroke in patients with atrial fibrillation (AF).

Food Interactions

Avoid St.John's Wort. Avoid alcohol. Avoid drastic changes in dietary habit. Consult your doctor before taking large amounts of Vitamin K (Green leafy vegetables). Limit garlic, ginger, gingko, and horse chestnut.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Metabolized by hepatic microsomal enzymes.

Protein Binding

99.5%

Half Life

1 week

Toxicity

LD₅₀=374 (orally in mice)

Chemical Properties

Chemical Formula:

C₁₉H₁₆O₄

SMILES Code:

CC(=O)CC(c1ccccc1)c2c(c3ccccc3oc2=O)O

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

308.3279 / 308.1049

In-Depth Annotations ()

1. rs1799853 at chr10:96692037 in CYP2C9
   This variant has been shown to influence warfarin dose as well as affecting the clearance of several other drugs.

   Variant Name:

   CYP2C9*2; CYP2C9:144Arg>Cys

   Related Drugs:

   fluvastatin, glipizide, phenytoin, tolbutamide, warfarin

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforCYP2C9-111
   

2. rs1057910 at chr10:96731043 in CYP2C9
   This variant has been shown to correlate significantly with warfarin dose as well as affecting the clearance of several other drugs.

   Variant Name:

   CYP2C9*3; CYP2C9:359Ile>Leu

   Related Drugs:

   fluvastatin, glipizide, phenytoin, tolbutamide, warfarin

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforCYP2C9-222
   

3. rs7294 at chr16:31009822 in VKORC1
   May be associated with a higher warfarin dose phenotype

   Variant Name:

   VKORC1:G9041A; VKORC1:3730G>A

   Related Drugs:

   warfarin

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforVKORC1-9041
   

4. rs9934438 at chr16:31012379 in VKORC1
   Tagging SNP for low dose phenotype

   Variant Name:

   VKORC1:C6484T; VKORC1:1173C>T

   Related Drugs:

   warfarin

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforVKORC1-6484
   

5. rs9923231 at chr16:31015190 in VKORC1
   Believed to be the causative allele for the low dose phenotype in warfarin therapy based on both in vitro and in vivo evidence

   Variant Name:

   VKORC1:G3673A; VKORC1:-1639G>A

   Related Drugs:

   warfarin

   Evidence:

   http://www.pharmgkb.org/.../variant.jsp#ImportantVariantInformationforVKORC1-3673
   

Curated Annotations ()

1. rs4653436 at chr1:224061834
   Risk or phenotype-associated allele: undetermined. Phenotype: The variant allele was not associated with warfarin maintenance dose variability (p = 0.4450). Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): not significant. Type of association: GN; PK.

   Variant Name:

   EPHX1, upstream G/A

   Related Drugs:

   warfarin

   Evidence:

   PMID:19794411
   

2. rs1051740 at chr1:224086256 in EPHX1
   Risk or phenotype-associated allele: C allele Phenotype: The C allele was not associated with warfarin maintenance dose variability (p = 0.5835). Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): not significant Type of association: GN; PK.

   Variant Name:

   EPHX1, exon 3, c.337T>C, mRNA 612T>C, mRNA 378T>C, p.Tyr113His

   Related Drugs:

   warfarin

   Evidence:

   PMID:19794411
   

3. rs2292566 at chr1:224086276 in EPHX1
   Risk or phenotype-associated allele: A allele. Phenotype: Carriers of either one or two alleles of the A allele required 19% lower warfarin maintenance dose (2.6 ± 1.3 mg) compared to GG homozygotes (3.2 ± 1.6 mg) (p < 0.0001). The combined effect of variants in four genes, as well as age, explained 26.6% of the overall interindividual warfarin dose variability, with VKORC1 (rs9923231 A allele) accounting for 19.1%, CYP2C9 (rs1799853 T allele, or rs1057910 C allele) for 3.2%, EPHX1 (rs2292566 A allele) for 1.7%, CYP4F2 (rs2108622 C allele) gentoypes for 1.1%, and age for 1.5%. Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): p < 0.0001. Type of association: GN; PK.

   Variant Name:

   EPHX1, exon 3, c.357G>A, mRNA 632G>A, mRNA 398G>A, p.Lys119Lys

   Related Drugs:

   warfarin

   Evidence:

   PMID:19794411
   

4. rs2260863 at chr1:224086397 in EPHX1
   Risk or phenotype-associated allele: undetermined. Phenotype: The variant allele was not associated with warfarin maintenance dose variability (p = 0.7223). Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): not significant. Type of association: GN; PK.

   Variant Name:

   EPHX1, intron 3 G/C

   Related Drugs:

   warfarin

   Evidence:

   PMID:19794411
   

5. rs2234922 at chr1:224093029 in EPHX1
   Risk or phenotype-associated allele: undetermined. Phenotype: The variant allele was not associated with warfarin maintenance dose variability (p = 0.5311). Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): not significant. Type of association: GN; PK.

   Variant Name:

   EPHX1, mRNA 691A>G, mRNA 457A>G, p.His139Arg

   Related Drugs:

   warfarin

   Evidence:

   PMID:19794411
   

6. rs12714145 at chr2:85640852 in GGCX
   Risk or phenotype-associated allele: undetermined. Phenotype: The variant allele was not associated with warfarin maintenance dose variability (p = 0.7669). Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): not significant. Type of association: GN; PK.

   Variant Name:

   GGCZ, intron 2 C/T

   Related Drugs:

   warfarin

   Evidence:

   PMID:19794411
   

7. rs2069919 at chr2:127896023 in PROC
   Risk or phenotype-associated allele: undetermined. Phenotype: The variant allele was not associated with warfarin maintenance dose variability (p = 0.7024). Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): not significant. Type of association: GN; PK.

   Variant Name:

   PROC, intron 3 G/A

   Related Drugs:

   warfarin

   Evidence:

   PMID:19794411
   

8. rs11653 at chr7:128196816 in CALU, OPN1SW
   Risk or phenotype-associated allele: undetermined. Phenotype: The variant allele was not associated with warfarin maintenance dose variability (p = 0.7123). Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): not significant. Type of association: GN; PK.

   Variant Name:

   CALU, 3'UTR T/A

   Related Drugs:

   warfarin

   Evidence:

   PMID:19794411
   

9. rs1687390 at chr9:116129709 in ORM1, ORM2
   Risk or phenotype-associated allele: undetermined. Phenotype: The variant allele was not associated with warfarin maintenance dose variability (p = 1). Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): not significant. Type of association: GN; PK.

   Variant Name:

   ORM1, downstream G/A

   Related Drugs:

   warfarin

   Evidence:

   PMID:19794411
   

10. rs1799853 at chr10:96692037 in CYP2C9
    This variant (CYP2C9*2) has been shown to influence warfarin dose and is included in the pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin.

    Variant Name:

    CYP2C9*2; CYP2C9:144Arg>Cys

    Related Drugs:

    warfarin

    Evidence:

    PMID:19228618
    

11. rs1799853 at chr10:96692037 in CYP2C9
    Risk or phenotype-associated allele: rs1799853 T allele Phenotype: CYP2C9 wild-type (reference) allele carriers required a mean warfarin dose of 3.2 ± 1.6 mg, whereas patients carrying one or two CYP2C9 variant alleles (CYP2C9*2 = rs1799853 T allele, CYP2C9*3 = rs1057910 C allele, relative to CYP2C9*1 = reference) required significantly lower doses (*1/*x: 2.7 ± 1.5 mg (−16%); *x/*x: 1.9 ± 1.1 mg (−41%)) (p = 0.0015). CYP2C9 genotypes showed significant influence on the time to the first INR >=2 (p = 0.0016). The risk for having an INR value >=4 was higher in individuals with multiple variants of CYP2C9 or VKORC1 (rs9923231 A allele) (OR = 12.8, 95% CI = 2.73-60.0). The combined effect of variants and age, explained 26.6% of the variability in the warfarin dose, with VKORC1 (rs9923231 A allele) accounting for 19.1%, CYP2C9 (rs1799853 T allele, or rs1057910 C allele) for 3.2%, EPHX1 (rs2292566 A allele) for 1.7%, CYP4F2 (rs2108622 C allele) for 1.1%, and age for 1.5%. Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): p < = 0.0016. Type of association: GN; PK.

    Variant Name:

    CYP2C9*2, c.430C>T, mRNA 455C>T, p.Arg144Cys

    Related Drugs:

    warfarin

    Evidence:

    PMID:19794411
    

12. rs7900194 at chr10:96692056 in CYP2C9
    Phenotype: In African Americans patients, weekly warfarin dose requirements were lower in those with the CYP2C9*8 allele (34 (30-47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28-40 mg); P < 0.001) as compared with those with the CYP2C9*1/*1 genotype (43 (35-56) mg). Adding the *5,*6,*8 and *11 alleles to a model containing the *2 and *3 alleles plus the VKORC1 -1639 G>A allele (along with clinical variables) explained 36% vs. 30% of the variability in dose requirements. Study size: 226 . Study population/ethnicity: African-American . Type of association: PD;GN;CO

    Variant Name:

    CYP2C9*8;CYP2C9:R150H

    Related Drugs:

    warfarin

    Related Diseases:

    Atrial Fibrillation, Pulmonary Embolism, Stroke, Venous Thrombosis

    Evidence:

    PMID:20072124
    

13. rs4086116 at chr10:96697192 in CYP2C9
    In a GWAS study, this SNP was modestly associated with warfarin dose, accounting for ~9% of the variance in dose. This SNP was in perfect linkage disequilibrium with rs4917639.

    Related Drugs:

    warfarin

    Evidence:

    PMID:18535201
    

14. rs9332131 at chr10:96699029 in CYP2C9
    Phenotype: In African Americans patients, weekly warfarin dose requirements were lower in those with the CYP2C9*8 allele (34 (30-47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28-40 mg); P < 0.001) as compared with those with the CYP2C9*1/*1 genotype (43 (35-56) mg). Adding the *5,*6,*8 and *11 alleles to a model containing the *2 and *3 alleles plus the VKORC1 -1639 G>A allele (along with clinical variables) explained 36% vs. 30% of the variability in dose requirements. Study size: 226 . Study population/ethnicity: African-American . Type of association: PD;GN;CO

    Variant Name:

    CYP2C9*6;CYP2C9:null allele

    Related Drugs:

    warfarin

    Related Diseases:

    Atrial Fibrillation, Pulmonary Embolism, Stroke, Venous Thrombosis

    Evidence:

    PMID:20072124
    

15. rs4917639 at chr10:96715525 in CYP2C9
    In a GWAS study, this SNP was modestly associated with warfarin dose, and was in perfect linkage disequilibrium with rs4086116.

    Variant Name:

    CYP2C9(*2*3 tag)

    Related Drugs:

    warfarin

    Evidence:

    PMID:18535201
    

16. rs28371685 at chr10:96730971 in CYP2C9
    Phenotype: In African Americans patients, weekly warfarin dose requirements were lower in those with the CYP2C9*8 allele (34 (30-47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28-40 mg); P < 0.001) as compared with those with the CYP2C9*1/*1 genotype (43 (35-56) mg). Adding the *5,*6,*8 and *11 alleles to a model containing the *2 and *3 alleles plus the VKORC1 -1639 G>A allele (along with clinical variables) explained 36% vs. 30% of the variability in dose requirements. Study size: 226 . Study population/ethnicity: African-American . Type of association: PD;GN;CO

    Variant Name:

    CYP2C9*11;CYP2C9:R335W

    Related Drugs:

    warfarin

    Related Diseases:

    Atrial Fibrillation, Pulmonary Embolism, Stroke, Venous Thrombosis

    Evidence:

    PMID:20072124
    

17. rs1057910 at chr10:96731043 in CYP2C9
    In a GWAS study, this SNP was modestly associated with warfarin dose.

    Variant Name:

    CYP2C9*3:Ile359Leu

    Related Drugs:

    warfarin

    Evidence:

    PMID:18535201
    

18. rs1057910 at chr10:96731043 in CYP2C9
    This variant (CYP2C9*3) has been shown to influence warfarin dose and is included in the pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin.

    Variant Name:

    CYP2C9*3; CYP2C9:359Ile>Leu

    Related Drugs:

    warfarin

    Evidence:

    PMID:19228618
    

19. rs1057910 at chr10:96731043 in CYP2C9
    Risk or phenotype-associated allele: rs1057910 C allele Phenotype: CYP2C9 wild-type (reference) allele carriers required a mean warfarin dose of 3.2 ± 1.6 mg, whereas patients carrying one or two CYP2C9 variant alleles (CYP2C9*2 = rs1799853 T allele, CYP2C9*3 = rs1057910 C allele, relative to CYP2C9*1 = reference) required significantly lower doses (*1/*x: 2.7 ± 1.5 mg (−16%); *x/*x: 1.9 ± 1.1 mg (−41%)) (p = 0.0015). CYP2C9 genotypes showed significant influence on the time to the first INR >=2 (p = 0.0016). The risk for having an INR value >=4 was higher in individuals with multiple variants of CYP2C9 or VKORC1 (rs9923231 A allele) (OR = 12.8, 95% CI = 2.73-60.0). The combined effect of variants and age, explained 26.6% of the variability in the warfarin dose, with VKORC1 (rs9923231 A allele) accounting for 19.1%, CYP2C9 (rs1799853 T allele, or rs1057910 C allele) for 3.2%, EPHX1 (rs2292566 A allele) for 1.7%, CYP4F2 (rs2108622 C allele) for 1.1%, and age for 1.5%. Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): p < = 0.0016. Type of association: GN; PK.

    Variant Name:

    CYP2C9*3, c.1075A>C, mRNA 11A>C, p.Ile359Leu

    Related Drugs:

    warfarin

    Evidence:

    PMID:19794411
    

20. rs28371686 at chr10:96731048 in CYP2C9
    Phenotype: In African Americans patients, weekly warfarin dose requirements were lower in those with the CYP2C9*8 allele (34 (30-47) mg; P = 0.023) and the CYP2C9 *2, *3, *5, *6, or *11 allele (33(28-40 mg); P < 0.001) as compared with those with the CYP2C9*1/*1 genotype (43 (35-56) mg). Adding the *5,*6,*8 and *11 alleles to a model containing the *2 and *3 alleles plus the VKORC1 -1639 G>A allele (along with clinical variables) explained 36% vs. 30% of the variability in dose requirements. Study size: 226 . Study population/ethnicity: African-American . Type of association: PD;GN;CO

    Variant Name:

    CYP2C9*5;CYP2C9:D360E

    Related Drugs:

    warfarin

    Related Diseases:

    Atrial Fibrillation, Pulmonary Embolism, Stroke, Venous Thrombosis

    Evidence:

    PMID:20072124
    

21. rs216013 at chr12:2599893 in CACNA1C
    This intronic variant in the membrane calcium-channel gene CACNA1C was correlated with warfarin dose (p = 9.2 × 10−5) in the index population (n = 181) from a GWAS study of white patients undergoing anticoagulation therapy. Combined analysis of the index and replication populations (n = 374) yielded a p value of 8.6 × 10−7. "However, this variant did not reach established significance threshold independently in the replication population (P = .002), nor did it achieve significance after multiple testing correction in multivariate modeling (uncorrected P = .003)".

    Related Drugs:

    warfarin

    Evidence:

    PMID:18535201
    

22. rs10871454 at chr16:30955580 in STX4
    In a GWAS study, this SNP accounted for ~25% of the variance in log-transformed stabilized warfarin dose, and was in perfect linkage disequilibrium with rs9923231 (VKORC1:-1639).

    Variant Name:

    STX4

    Related Drugs:

    warfarin

    Evidence:

    PMID:18535201
    

23. rs7200749 at chr16:31010090 in VKORC1
    This SNP is the tagging SNP for VKORC1*3F (with 20% allele frequency in africans (AFR).

    Variant Name:

    VKORC1:3462C>T; 8773C>T

    Related Drugs:

    warfarin

    Evidence:

    PMID:16270629
    

24. rs2359612 at chr16:31011297 in VKORC1
    This SNP is the tagging SNP for VKORC1*2.

    Variant Name:

    VKORC1: 2255C>T; 7566C>T

    Related Drugs:

    warfarin

    Evidence:

    PMID:16270629
    

25. rs8050894 at chr16:31012010 in VKORC1
    This SNP is the tagging SNP for VKORC1*4.

    Variant Name:

    VKORC1: 1542G>C; 6853G>C

    Related Drugs:

    warfarin

    Evidence:

    PMID:16270629
    

26. rs17708472 at chr16:31012854 in VKORC1
    This SNP is the tagging SNP for VKORC1*2.

    Variant Name:

    VKORC1: 6009C>T; 698C>T

    Related Drugs:

    warfarin

    Evidence:

    PMID:16270629
    

27. rs28940304 at chr16:31013380 in VKORC1
    This rare (<0.1%) missense mutation in VKORC1 gene confers warfarin resistance phenotype. Individuals carrying this mutation require higher dose of warfarin (32-36mg/d).

    Variant Name:

    VKORC1:R58G; Arg58Gly

    Related Drugs:

    warfarin

    Evidence:

    PMID:14765194
    PMID:18234405
    

28. rs28940303 at chr16:31013418 in VKORC1
    This rare (<0.1%) missense mutation in VKORC1 gene confers severe warfarin resistance phenotype. Individuals carrying this mutation require higher dose of warfarin (Target INR never reached).

    Variant Name:

    VKORC1:V45A; Val45Ala

    Related Drugs:

    warfarin

    Evidence:

    PMID:14765194
    PMID:18234404
    

29. rs28940302 at chr16:31013467 in VKORC1
    This rare (<0.1%) missense mutation in VKORC1 gene confers warfarin resistance phenotype. Individuals carrying this mutation require higher dose of warfarin (14mg/d).

    Variant Name:

    VKORC1: V29L; Val29Leu

    Related Drugs:

    warfarin

    Evidence:

    PMID:14765194
    PMID:18234403
    

30. rs9923231 at chr16:31015190 in VKORC1
    In a GWAS study, this SNP was strongly associated with stabilized warfarin dose, and was in perfect linkage disequilibrium with rs10871454.

    Variant Name:

    VKORC1:-1639

    Related Drugs:

    warfarin

    Evidence:

    PMID:18535201
    

31. rs9923231 at chr16:31015190 in VKORC1
    This promoter SNP is believed to be the causative SNP for the warfarin low dose phenotype. It is included in the pharmacogenetic algorithm for estimating the appropriate initial dose of warfarin.

    Variant Name:

    VKORC1:G3673A; VKORC1:-1639G>A

    Related Drugs:

    warfarin

    Evidence:

    PMID:19228618
    

32. rs9923231 at chr16:31015190 in VKORC1
    Risk or phenotype-associated allele: A allele Phenotype: This A allele was associated with a lower warfarin maintenance dose according to a gene-dose effect (1.9 ± 1.2 mg (−50%) for AA homozygotes, 2.8 ± 1.3 mg (−26%) for GA heterozygotes, 3.8 ± 1.6 mg in GG homozygotes) (p < 0.0001). The A allele was associated with shorter median time to the first INR >=2 (3 vs. 6 vs. 8 days for AA, GA, and GG genotypes, respectively) (p = 0.0003). Risk for having an INR value >=4 was higher in individuals the A allele or CYP2C9 variants (rs1799853 T allele, rs1057910 C allele) (OR = 12.8; 95% CI = 2.73-60.0). The combined effect of variants and age explained 26.6% of the warfarin dose variability, with VKORC1 (rs9923231 A allele) accounting for 19.1%, CYP2C9 (rs1799853 T allele, or rs1057910 C allele) for 3.2%, EPHX1 (rs2292566 A allele) for 1.7%, CYP4F2 (rs2108622 C allele) for 1.1%, and age for 1.5%. Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): p < = 0.003. Type of association: GN; PK.

    Variant Name:

    upstream -1639G>A

    Related Drugs:

    warfarin

    Evidence:

    PMID:19794411
    

33. rs2108622 at chr19:15851431 in CYP4F2
    This variant is found to have clinical impact on stable warfarin dose. Patients with 2 TT alleles were reported to require approximately 1 mg/day more warfarin than patients with 2 CC alleles. This variant affects enzyme acitivity and was shown to decrease 20-HETE production in a reconstituted recombinant protein system to approximately 60% of the wild-type enzyme.

    Variant Name:

    CYP4F2:V433M

    Related Drugs:

    warfarin

    Evidence:

    PMID:17341693
    PMID:18250228
    

34. rs2108622 at chr19:15851431 in CYP4F2
    An in-vitro study demonstrated that CYP4F2 is a vitamin K(1) oxidase and that carriers of the CYP4F2 V433M allele have a reduced capacity to metabolize vitamin K. Secondary, this variant causes a decrease in steady-state hepatic concentrations of the enzyme.

    Variant Name:

    CYP4F2: V433M

    Related Drugs:

    warfarin

    Evidence:

    PMID:19297519
    

35. rs2108622 at chr19:15851431 in CYP4F2
    Risk or phenotype-associated allele: A allele Phenotype: The A allele was not associated with variability in warfarin maintenance dose (p = 0.1270), however the combined effect of variants and age explained 26.6% of the overall interindividual in warfarin dose variability, with VKORC1 (rs9923231 A allele) accounting for 19.1%, CYP2C9 (rs1799853 T allele, or rs1057910 C allele) for 3.2%, EPHX1 (rs2292566 A allele) for 1.7%, CYP4F2 (rs2108622 C allele) gentoypes for 1.1%, and age for 1.5%. Study size: 283. Study population/ethnicity: Hospitalized Caucasian patients aged 75 years or older, recruited Sep 2002-Nov 2004 in Ivry, France, and Oct 2005-Mar 2008 from 14 French centers. Significance metric(s): mixed. Type of association: GN; PK.

    Variant Name:

    CYP4F2 exon 11, c.1297G>A, mRNA 1347G>A, p.Val433Met

    Related Drugs:

    warfarin

    Evidence:

    PMID:19794411
    

Non-Curated Annotations ()

1. rs1799853 at chr10:96692037 in CYP2C9
   GWAS results: A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose. (Initial Sample Size: 1,053 individuals; Replication Sample Size: 588 individuals); (Region: 10q23.33; Reported Gene(s): CYP2C9; Risk Allele: rs1799853-?); (p-value= 1E-31).This variant is associated with Warfarin maintenance dose.

   Related Drugs:

   warfarin

   Evidence:

   PMID:19300499
   http://www.genome.gov/gwastudies/
   

2. rs1057910 at chr10:96731043 in CYP2C9
   GWAS results: A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose. (Initial Sample Size: 1,053 individuals; Replication Sample Size: 588 individuals); (Region: 10q23.33; Reported Gene(s): CYP2C9; Risk Allele: rs1057910-?); (p-value= 3E-79).This variant is associated with Warfarin maintenance dose.

   Related Drugs:

   warfarin

   Evidence:

   PMID:19300499
   http://www.genome.gov/gwastudies/
   

3. rs216013 at chr12:2599893 in CACNA1C
   GWAS results: A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose (Initial Sample Size: 181 individuals; Replication Sample Size: 374 individuals). This variant is associated with Warfarin maintenance dose.

   Related Drugs:

   warfarin

   Evidence:

   PMID:18535201
   http://www.genome.gov/gwastudies/
   

4. rs9923231 at chr16:31015190 in VKORC1
   GWAS results: A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose. (Initial Sample Size: 1,053 individuals; Replication Sample Size: 588 individuals); (Region: 16p11.2; Reported Gene(s): VKORC1; Risk Allele: rs9923231-T); (p-value= 0).This variant is associated with Warfarin maintenance dose.

   Related Drugs:

   warfarin

   Evidence:

   PMID:19300499
   http://www.genome.gov/gwastudies/
   

5. rs2108622 at chr19:15851431 in CYP4F2
   GWAS results: A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose. (Initial Sample Size: 1,053 individuals; Replication Sample Size: 588 individuals); (Region: 19p13.12; Reported Gene(s): CYP4F2; Risk Allele: rs2108622-?); (p-value= 0.0000000003).This variant is associated with Warfarin maintenance dose.

   Related Drugs:

   warfarin

   Evidence:

   PMID:19300499
   http://www.genome.gov/gwastudies/
   

Curated Information

The following genes are in curated knowledge about this drug.

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Metabolizing Enzymes

• CYP1A2
• CYP2C9
• CYP2C8

Drug Targets

• F2
• VKORC1
• VKORC1L1

PharmGKB Curated Pathways

• Warfarin Pathway (PD)
• Warfarin Pathway (PK)

Curated Information

The following drugs are in curated knowledge about this drug.

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this drug.

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Curated Phenotype Datasets

These datasets are sorted alphabetically by title.

1. IWPC Warfarin Data Set (NEJM 2009)

   • 
   • 
   • 
   • 
   • PD
   • PK
   • GN

   Submitted by Warfarin Consortium involving CYP2C9, VKORC1, amiodarone, aspirin, simvastatin, warfarin, and Atrial Fibrillation
2. Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin

   • 
   • 
   • 
   • 
   • PD
   • PK
   • GN

   Submitted by Brian Gage, MD involving CYP2C9, VKORC1, amiodarone, aspirin, simvastatin, warfarin, , Atrial Fibrillation, post-orthopedic, Pulmonary Embolism, Stroke and Venous Thrombosis
3. WashU Pharmacogenetic Warfarin Dose Adjustment Phenotype Data

   • 
   • 
   • 
   • 
   • PD
   • PK

   Submitted by Brian Gage, MD involving warfarin, , Atrial Fibrillation and Venous Thrombosis
4. WUSTL warfarin dosing data, group A

   • 
   • 
   • 
   • 
   • PD
   • PK

   Submitted by Brian Gage, MD involving VKORC1, warfarin, and Atrial Fibrillation

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. Genetic Determinants of Initial Warfarin Response
2. Genetic Variants associated with Warfarin Response
3. IWPC Pharmacogenetic Dosing Algorithm
4. Physicochemical determinants of human renal clearance
5. Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.