Gene:
CYP4F2
cytochrome P450, family 4, subfamily F, polypeptide 2

Available Prescribing Info

Dosing Guidelines
  1. Annotation of CPIC Guideline for warfarin and CYP2C9,CYP4F2,VKORC1
last updated 02/08/2017

1. Annotation of CPIC Guideline for warfarin and CYP2C9,CYP4F2,VKORC1

Summary

The updated guideline for pharmacogenetics-guided warfarin dosing is published by the Clinical Pharmacogenetics Implementation Consortium. The recommendations for dosing are for adult and pediatric patients that are specific to continental ancestry, and are based on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823.

Annotation

This annotation is based on the CPIC® guideline for pharmacogenetics-guided warfarin dosing.

February 2017 Update

  • The 2017 update of CPIC guidelines regarding the use of pharmacogenomic tests in dosing of warfarin is published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC). Literature up to Dec 2016 was reviewed, recommendations and supplemental information were updated.

  • Excerpt from the 2017 dosing guideline update:

    • "Therapeutic Recommendations: Adults
      Numerous studies have derived warfarin dosing algorithms that use both genetic and non-genetic factors to predict warfarin dose [Articles:18305455, 19228618, 20375999, 22012312]. Two algorithms perform well in estimating stable warfarin dose [Articles:18305455, 19228618] and were created using more than 5,000 subjects, though as noted above, more recent data suggest they do not perform acceptably in African Americans when used without modification for CYP2C9 alleles frequently found in the African population [Article:24251361]. The Gage and IWPC algorithms or minor adjustments to them have also been the algorithms used in both randomized controlled trials and most of the prospective dosing studies. Dosing algorithms using genetic information outperform non-genetic clinical algorithms and fixed-dose approaches in dose prediction, except in African Americans when the algorithm only includes CYP2C9*2 and *3 [Articles:18305455, 19228618, 24251361]. Genetics-based algorithms also better predict warfarin dose than the FDA-approved warfarin label table [Article:21272753].

      Pharmacogenetic algorithm-based warfarin dosing: This guideline recommends that pharmacogenetic warfarin dosing be accomplished through the use of one of the pharmacogenetic dosing algorithms described above, as summarized in Figure 2. The two algorithms provide very similar dose recommendations...It is important to note that these algorithms do not include CYP4F2, CYP2C9*5, *6, *8, or *11 or rs12777823, and incorporation of these should be added when results are available, as described in Figure 2. The warfarindosing.org website contains both algorithms, the Gage algorithm [Article:18305455] as the primary algorithm and the IWPC algorithm [Article:19228618] as the secondary algorithm and can adjust for CYP4F2, CYP2C9*5 and *6. If utilizing warfarindosing.org, the user should be clear on whether the algorithm is or is not incorporating genotypes beyond CYP2C9 *2 and *3 and VKORC1, which are the only three genotypes in the original version of both algorithms.

      Non-African ancestry recommendation. In patients who self-identify as non-African ancestry, the recommendation, as summarized in Figure 2, is to: 1) calculate warfarin dosing using a published pharmacogenetic algorithm [Articles:18305455, 19228618], including genotype information for VKORC1-1639G>A and CYP2C9*2 and *3. In individuals with genotypes associated with CYP2C9 poor metabolism (e.g., CYP2C9 *2/*3, *3/*3) or both increased sensitivity (VKORC1-1639 A/A) and CYP2C9 poor metabolism, an alternative oral anticoagulant might be considered. These recommendations are graded as STRONG. 2) If a loading dose is to be utilized, the EU-PACT loading dose algorithm that incorporates genetic information could be used [Article:24251363]. This recommendation is OPTIONAL. 3) While CYP2C9*5, *6, *8, or*11 variant alleles are commonly referred to as African specific alleles, they can occur among individuals who do not identify as, or know of their, African ancestry. If these variant alleles are detected, decrease calculated dose by 15-30% per variant allele or consider an alternative agent. Larger dose reductions might be needed in patients homozygous for variant alleles (i.e. 20-40%, e.g. CYP2C9*2/*5). This recommendation is graded as OPTIONAL. 4) If the CYP4F2*3 (i.e., c.1297A, p.433Met) allele is also detected, increase the dose by 5-10%. This recommendation is also considered OPTIONAL. 5) The data do not suggest an association between rs12777823 genotype and warfarin dose in non-African Americans, thus rs12777823 should not be considered in these individuals (even if available).

      African ancestry recommendation. In patients of African ancestry, CYP2C9*5, *6, *8, *11 are important for warfarin dosing. If these genotypes are not available, warfarin should be dosed clinically without consideration for genotype. If CYP2C9*5, *6, *8, and *11 are known, then the recommendation, as shown in Figure 2, is to: 1) calculate warfarin dose using a validated pharmacogenetic algorithm, including genotype information for VKORC1 c.-1639G>A and CYP2C9*2 and *3 [Articles:18305455, 19228618]; 2) if the individual carriers a CYP2C9*5, *6, *8, or *11 variant allele(s), decrease calculated dose by 15-30%. Larger dose reductions might be needed in patients who carry two variant alleles (e.g., CYP2C9*5/*6) (i.e. 20-40% dose reduction). 3) In addition, rs12777823 is associated with warfarin dosing in African Americans (mainly originating from West Africa). Thus, in African Americans a dose reductions of 10-25% in those with rs12777823 A/G or A/A genotype is recommended. These recommendations are considered MODERATE. In individuals with genotypes that predict CYP2C9 poor metabolism or who have increased warfarin sensitivity (VKORC1 c.-1639 A/A) and CYP2C9 poor metabolism, an alternative oral anticoagulant should be considered."

    • "Therapeutic Recommendations: Pediatric
      In children of European ancestry and if CYP2C9*2 and *3 and VKORC1-1639 genotype are available, calculate warfarin dosing based on a validated published pediatric pharmacogenetic algorithm (Figure 3) [Articles:22010099, 23307232]. A dosing tool that can be used in children of European ancestry is available at http://www.warfarindoserevision.com [Article:24330000]."

  • Download and read:

Figure 2. Dosing recommendations for Warfarin dosing based on genotype for adult patients

Adapted from Figure 2 of the 2017 guideline manuscript

Fig2

Figure 2 Legend: a“Dose clinically” means to dose without genetic information, which may include use of a clinical dosing algorithm or standard dose approach
bData strongest for European and East Asian ancestry populations and consistent in other populations.
c45-50% of individuals with self-reported African ancestry carry CYP2C9*5,*6,*8,*11, or rs12777823. IF CYP2C9*5, *6, *8, and *11 WERE NOT TESTED, DOSE WARFARIN CLINICALLY. Note: these data derive primarily from African Americans, who are largely from West Africa. It is unknown if the same associations are present for those from other parts of Africa.
dMost algorithms are developed for the target INR 2-3.
eConsider an alternative agent in individuals with genotypes associated with CYP2C9 poor metabolism (e.g., CYP2C9*3/*3, *2/*3, *3/*3) or both increased sensitivity (VKORC1 A/G or A/A) and CYP2C9 poor metabolism.
fSee the EU-PACT trial for pharmacogenetics-based warfarin initiation (loading) dose algorithm [Article:24251363] with the caveat that the loading dose PG algorithm has not been specifically tested or validated in populations of African ancestry.
gLarger dose reduction might be needed in variant homozygotes (i.e. 20-40%).
hAfrican American refers to individuals mainly originating from West Africa.

Figure 3. Dosing recommendations for Warfarin dosing based on genotype for pediatric patients

Adapted from Figure 3 of the 2017 guideline manuscript

Fig3

Figure 3 Legend: aData strongest for European ancestry populations and consistent in most Japanese studies.
b“Dose clinically” means to dose without genetic information, which may include use of a clinical dosing algorithm or standard dose approach
cValidated published pediatric pharmacogenetic algorithms include Hamberg et al.[Article:24330000] and Biss et al.[Article:22010099]
dNo studies in children included CYP2C9*5, *6, *8, or *11 genotyping.

November 2013 Update

CPIC guideline authors are aware of several recently published studies on warfarin pharmacogenetics [Articles:24251361, 24251363, 24251360]. These papers have prompted several opinion pieces [Articles:24328463, 24251364]. The authors are evaluating the information, which will be incorporated into the next update of the CPIC guideline on warfarin.

October 2011

Advance online publication September 2011.

  • Guideline regarding the use of pharmacogenomic tests in dosing for warfarin was published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
  • These guidelines are applicable to:
    • adult patients
  • Excerpt from the 2011 warfarin dosing guideline:
    • "Pharmacogenetic algorithm-based warfarin dosing: Numerous studies have derived warfarin dosing algorithms that use both genetic and non-genetic factors to predict warfarin dose [Articles:18305455, 19228618, 18574025]. Two algorithms perform well in estimating stable warfarin dose across different ethnic populations; [Articles:18305455, 19228618] these were created using more than 5,000 subjects. Dosing algorithms using genetics outperform nongenetic clinical algorithms and fixed-dose approaches in dose prediction [Articles:18305455, 19228618]. The best way to estimate the anticipated stable dose of warfarin is to use the algorithms available on http://www.warfarindosing.org (offering both high-performing algorithms [Articles:18305455, 19228618]). The dosing algorithm published by the International Warfarin Pharmacogenetics Consortium is also online, at IWPC Pharmacogenetic Dosing Algorithm. The two algorithms provide very similar dose recommendations."
    • "Approach to pharmacogenetic-based warfarin dosing without access to dosing algorithms: In 2007, the FDA modified the warfarin label, stating that CYP2C9 and VKORC1 genotypes may be useful in determining the optimal initial dose of warfarin [Article:17906972]. The label was further updated in 2010 to include a table (Table 1) describing recommendations for initial dosing ranges for patients with different combinations of CYP2C9 and VKORC1 genotypes. Genetics-based algorithms also better predict warfarin dose than the FDA-approved warfarin label table [Article:21272753]. Therefore, the use of pharmacogenetic algorithm-based dosing is recommended when possible, although if electronic means for such dosing are not available, the table-based dosing approaches (Table 1) are suggested. The range of doses by VKORC1 genotype and the range of dose recommendations/predictions by the FDA table and algorithm are shown in Figure 2."
  • Download and read:

Figure 2. Frequency histograms of stable therapeutic warfarin doses in mg/week, stratified by VKORC1 -1639G>A genotype.

Adapted from Figure 2 of the 2011 guideline manuscript

CPIC warfarin dosing guideline

Figure 2 Legend: Frequency histograms of stable therapeutic warfarin doses in mg/week, stratified by VKORC1 -1639G>A genotype in 3,616 patients recruited by the International Warfarin Pharmacogenetics Consortium (IWPC) who did not carry the CYP2C9*2 or *3 allele (i.e., coded as *1/*1 for US Food and Drug Administration (FDA) table and algorithm dosing). The range of doses within each genotype group recommended on the FDA table is shown via the shaded rectangle. The range of doses predicted using the IWPC dosing algorithm in these 3,616 patients is shown by the solid lines.

Figure 2 demonstrates that the range of individuals covered by the FDA table is much narrower than that of the algorithm. The article and supplement detail important variables that are not covered by the table that should also be taken into consideration.

Adapted from Table 1 of the 2011 guideline manuscript

VKORC1 Genotype (-1639G>A, rs9923231)CYP2C9*1/*1CYP2C9*1/*2CYP2C9*1/*3CYP2C9*2/*2CYP2C9*2/*3CYP2C9*3/*3
GG5-75-73-43-43-40.5-2
GA5-73-43-43-40.5-20.5-2
AA3-43-40.5-20.5-20.5-20.5-2

Reproduced from updated warfarin (Coumadin) product label.

Supplemental Table S1. Genotypes that constitute the * alleles for CYP2C9

Adapted from Table S1 of the 2011 guideline supplement

AlleleConstituted by genotypes at:Amino acid changesEnzymatic Activity
*1reference allele at all positionsNormal
*2C>T at rs1799853R144CDecreased
*3A>C at rs1057910I359LDecreased

PharmGKB has no annotated drug labels with pharmacogenomic information for this . If you know of a drug label with PGx, send us a message.

Clinical Variants that meet the highest level of criteria, manually curated by PharmGKB, are shown below. Please follow the link in the "Position" column for more information about a particular variant. Each link in the "Position" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the table.

Clinical Annotation for rs2108622 (CYP4F2), warfarin, Heart Diseases, Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Peripheral Vascular Diseases, Thromboembolism and venous thromboembolism (level 1B Dosage)

Level of Evidence
Level 1B
Type
Dosage
Variant
rs2108622
Genes
CYP4F2
Phenotypes
Heart Diseases, Hemorrhage, Intracranial Hemorrhages, Myocardial Infarction, Peripheral Vascular Diseases, Thromboembolism, venous thromboembolism
OMB Race
Mixed Population
Race Notes
Studies include White, Black or African American, Asian, Hispanic or Latino and Mixed populations.

To see the rest of this clinical annotation please register or sign in.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page on the appropriate tab.

Links in the "Drugs" column lead to PharmGKB Drug Pages.

List of all variant annotations for CYP4F2

Variant?
(147)
Alternate Names ? Chemicals ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No VIP available VA *1 N/A N/A N/A
No VIP available No VIP available VA *3 N/A N/A N/A
rs2108622 NC_000019.10:g.15879621C>T, NC_000019.9:g.15990431C>T, NG_007971.2:g.23454G>A, NM_001082.4:c.1297G>A, NP_001073.3:p.Val433Met, rs116975254, rs52819608, rs57319528
C > T
SNP
V433M
No VIP available CA VA
rs2108623 NC_000019.10:g.15906196G>A, NC_000019.9:g.16017006G>A, rs17454858, rs3947944, rs4429395, rs59294251
G > A
SNP
No VIP available CA VA
rs2189784 NC_000019.10:g.15848390G>A, NC_000019.9:g.15959200G>A, rs60426306
G > A
SNP
No VIP available CA VA
rs3093105 NC_000019.10:g.15897578A>C, NC_000019.9:g.16008388A>C, NG_007971.2:g.5497T>G, NM_001082.4:c.34T>G, NP_001073.3:p.Trp12Gly, rs117322022
A > C
SNP
W12G
No VIP available No Clinical Annotations available VA
rs3093135
A > T
SNP
No VIP available No Clinical Annotations available VA
rs3093158 NC_000019.10:g.15889356C>T, NC_000019.9:g.16000166C>T, NG_007971.2:g.13719G>A, NM_001082.4:c.918+67G>A, rs58337631
C > T
SNP
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 147

Overview

Alternate Names:  None
Alternate Symbols:  None
PharmGKB Accession Id: PA27121

Details

Cytogenetic Location: chr19 : p13.12 - p13.12
GP mRNA Boundary: chr19 : 15988834 - 16008884
GP Gene Boundary: chr19 : 15985834 - 16018884
Strand: minus

Visualization

UCSC has a Genome Browser that you can use to view PharmGKB annotations for this gene in context with many other sources of information.

View on UCSC Browser
The mRNA boundaries are calculated using the gene's default feature set from NCBI, mapped onto the UCSC Golden Path. PharmGKB sets gene boundaries by expanding the mRNA boundaries by no less than 10,000 bases upstream (5') and 3,000 bases downstream (3') to allow for potential regulatory regions.

Cytochrome p450, family 2, subfamily F, polypeptide 2 catalyzes the NADPH-dependent oxidation of the terminal carbon of long and very long-chain fatty acids, the side chains of vitamin K (K 1, K 2 ) and vitamin E (tocopherols and tocotrienols), arachidonic acid (AA), and leukotriene B 4 (LTB 4). CYP4F2 localizes to the endoplasmic reticulum of cells. Although it is predominantly expressed in the liver and kidneys, there is some evidence that CYP4F2 is expressed in human enteric microsomes [Articles:17709372, 24870542]. In the liver and kidneys CYP4F2 catalyzes the synthesis of 20-hydroxyeicosatetraeonic acid (20-HETE) from AA. Hepatic CYP4F2 also regulates the bioavailability of vitamin K and vitamin E, catalyzes the inactivation of LTB 4, and the bioactivation of the anti-malarial drug pafuramidine. Although initial studies of CYP4F2 were focused on its role as a regulator of LTB 4 and 20-HETE levels, current investigations focus on how genetic variants of CYP4F2 affect warfarin drug dosing and safety.

Substrates of CYP4F2

Fatty Acids
Fatty acids (FA) can be degraded by α, β, and ω-oxidation of their carbon chains. The preferred pathway of fatty acid degradation is β-oxidation in the mitochondria and peroxisomes. Very long chain fatty acids (VLCFAs), which are fatty acids with more than 22 carbons in their chain, cannot be β-oxidized and must be chain-shortened before they can be oxidized by the mitochondria. CYP4F2 contributes to FA oxidation by catalyzing the ω-oxidation and chain shortening of VLCFAs [Articles:18182499, 18433732]. Under normal physiologic conditions, ω-hydroxylation contributes somewhere between 4-15% of FA metabolism, but there is evidence supporting an increasingly larger role for CYP4F2 in FA metabolism during periods of fasting, upon administration of lovastatin, and as a rescue pathway in disorders of peroxisomal β-oxidation [Articles:18433732, 17786636, 22484021].

Eicosanoids
AA is a precursor of the eicosanoids, which are signaling molecules that mediate the inflammation and immune response. Acute inflammation at the site of injury or infection protects the body from pathogens but prolonged inflammation damages healthy cells and tissue; thus inflammation must be tightly controlled. LTB 4 is a pro-inflammatory eicosanoid that induces activation of polymorphonuclear leukocytes, monocytes, and fibroblasts, generation of superoxide, and the release of cytokines to attract neutrophils [Article:16926051]. ω -oxidation of LTB 4 is catalyzed by multiple members of the CYP4F family, but in the liver CYP4F2 is the principle enzyme to ω -oxidize LTB 4 to 20-OH LTB 4 , a far less potent eicosanoid metabolite [Articles:18433732, 17341693, 9799565, 11368003].

CYP4F2 also catalyzes the ω-oxidation of AA, which converts it to the signaling molecule 20-hydroxyeicosatetraeonic acid (20-HETE). 20-HETE promotes vasoconstriction by contributing to the myogenic response and by inducing alterations smooth muscle calcium homeostasis, which sensitize the smooth muscle to constrictor stimuli such as angiotensin II, phenylephrine and endothelin. In the nephron, 20-HETE is present in the proximal tubules, the thick ascending loop of Henle (TALH), and the glomerulus and it promotes natriuresis by acting on various ion transporters [Articles:23584425, 16258232]. Because 20-HETE is both vasoconstrictive and natriuretic its overall effect on arterial blood pressure depends on where it is acting, but the mechanism regulating the localization of its expression is still unknown.

Studies in rats and mice have shown that decreased levels of renal 20-HETE are associated with salt-sensitive hypertension whereas increased levels of renal 20-HETE are associated with other types of hypertension (e.g. spontaneous or androgen induced hypertension) [Articles:12874093, 20930591]. Multiple studies have reported that urinary 20-HETE is positively associated with hypertension in humans. If urinary 20-HETE reflects vascular 20-HETE levels it would provide a reasonable explanation for the positive association between urinary 20-HETE and increased blood pressure [Articles:18235092, 24984178, 18391101] or impaired vascular function [Article:15262846]. Unfortunately, the relationship between urinary 20-HETE levels and CYP4F2 enzyme activity is equivocal. One study reported that a haplotype shown to increase CYP4F2 expression (which is presumed to increase renal 20-HETE formation) was associated with increased urinary 20-HETE excretion and increased risk for hypertension [Article:18235092]. A second study reported that a single nucleotide polymorphism (SNP) in CYP4F2, which has been shown to decrease 20-HETE formation in vitro [Article:17341693], was also associated with increased urinary 20-HETE and increased blood pressure [Article:18391101].

Blood pressure is a sexually dimorphic characteristic; on average men under the age of 60 have higher blood pressure than age-matched pre-menopausal women [Articles:7875754, 18259027]. A study in male Sprague-Dawley rats showed that administration of 5 α -dihydrotestosterone stimulated production of 20-HETE in the renal vasculature, which preceded a statistically significant rise in systolic blood pressure. The rise in systolic blood pressure was abrogated upon administration of a 20-HETE antagonist [Article:21321301]. Several studies have also reported sex-specific associations between certain genetic variants of CYP4F2 with blood pressure, vascular function and risk of cerebral infarction [Articles:18391101, 15262846, 18787519, 18971550].

Vitamin E
Vitamin E is the name given to eight fat-soluble tocopherols and tocotrienols. Tocopherols are the most investigated form of vitamin E. Vitamin E is best known as a free-radical scavenger that prevents cellular peroxidation of polyunsaturated fatty acids (PUFA). Vitamin E is especially important for protecting the cell membranes of neurons and patients with perturbations in vitamin E absorption are at an increased risk of peripheral neuropathy and ataxia [Article:21664268]. α-tocopherol is the most biologically active of the four isomers of tocopherol: α, β, γ, δ. Each isomer differs in both the placement, and the number of hydroxyl groups on their chromanol rings. Studies have shown that regardless of the isoform of vitamin E consumed, the α-tocopherol isoform is always the predominant isoform in plasma and tissue [Article:23505319]. Tocopherols, like LCFAs and VLCFAs, are metabolized by chain shortening [Articles:15753130, 11997390]. Parker RS et al. were the first to report that the γ and δ tocopherols are preferentially catabolized over α-tocopherol, which promotes the retention of α-tocopherol in plasma and tissues. CYP4F2 is the only known enzyme to ω-hydroxylate vitamin E (tocotrienols as well as tocopherols), thus making it a critical modulator of circulating plasma vitamin E levels [Articles:15753130, 18433732, 20861217].

Vitamin K
Vitamin K refers to a group of fat-soluble derivatives of naphthoquinones, which differ in the number of double bonds present in their hydrocarbon chains. Plants synthesize vitamin K1 (VK 1), also known as phylloquinone. VK 1 is highly concentrated in leaves where it acts as an electron acceptor in the light dependent reactions of photosynthesis. Menaquinones, also known as vitamin K 2, are the main form of vitamin K in animals and the most common form is menaquinone 4 (MK-4), which can be synthesized from VK 1, and obtained by eating dark green leafy vegetables. Animals also obtain menaquinones from eating fermented food, and animal products [Article:18841274]. Both types of vitamin K can act as co-factors for γ-glutamyl carboxylase (GGCX), which catalyzes the biochemical activation of proteins involved in blood clotting, and bone mineralization. CYP4F2 ω-hydroxylates and inactivates vitamin K, which makes CYP4F2 an important negative regulator of vitamin K levels [Articles:23132553, 19297519, 24138531].

Anti-Parasitic Drugs
Pafuramidine (DB289), is a pro-drug of the anti-parasitic drug furamidine (DB75). Two studies identified CYP4F2 as one of the enzymes responsible for catalyzing the first-pass biotransformation of pafuramidine to furamidine in human liver microsomes and human enteric microsomes [Articles:17709372, 16997912].

The CYP4F2 Gene
CYP4F2 is part of a cluster of CYP4F genes on chromosome 19p13. The genetic architecture of all CYP4F genes is highly similar and the genes are thought to have evolved by duplication. Human CYP4F2 spans 2.2 kB, has thirteen exons, twelve introns, and its open reading frame is encoded between exons two and thirteen [Article:10492403]. The amino acid sequences of CYP4F2 and CYP4F3 are reported to be between 81-93% similar [Articles:17786636, 18662666, 10492403]. Analyses of the upstream 5' regions of CYP4F2 show that there are putative RXRα and RARα response elements (RARE), sterol regulatory element binding protein elements (SREBPE), nuclear factor κ Β and Myb response elements [Articles:18235092, 10492403, 18662666].

Hirani and colleagues (2008) developed a targeted polyclonal antibody of CYP4F2 to quantify CYP4F2 protein levels in human liver and kidney cortex samples [Article:18662666]. With this antibody substantial inter-individual variability in CYP4F2 expression from liver and kidney samples was discovered. Microsomal protein levels of CYP4F2 ranged between 0-80.1 pmol/mg protein in liver and between 0-11.3 pmol/ mg protein in kidney cortex. Total hepatic microsomal immunoreactive CYP4F (CYP4F3b, CYP4F11, CYP4F12) protein was present in all patients, even those without detectable CYP4F2 protein. This evidence suggests that CYP4F2 may be regulated in a different manner than other CYP4F family members [Article:18662666].

Inducers and inhibitors of CYP4F2
The molecular mediators that regulate CYP4F2 expression have only been elucidated in in vitro systems. Studies in hepatoblastoma cell lines (HepG2) have shown that retinoic acid regulates CYP4F2 transcription through the RXRα and RARα nuclear receptors. A study using a luciferase reporter system in HepG2 cells that were transiently transfected with the upstream CYP4F2 regions -506/6 and -1726/6 revealed that co-transfection with human RXR α, and all-trans retinoic acid (ATRA), or 9-cis-retinoic acid (9cRA) stimulated reporter activity [Article:11162441]. In contrast, co-transfection of either 9cRA or ATRA and RAR α, or RXR α/RAR α heterodimers attenuated the observed increase in promoter activity. The same study also identified several putative retinoic response elements (RARE) near CYP4F2, but none were confirmed RAREs. Although both retinoic acids induced promoter construct activity, only 9cRA was capable of inducing protein translation of CYP4F2 [Article:1116244]. Saturated fatty acids, such as lauric acid and stearic acid also induced CYP4F2 expression in HepG2 cells [Article:10860554]. The promoter region of CYP4F2 contains multiple sterol regulatory element binding protein (SREBP) elements. SREBP-2 was found to mediate lovastatin-induced expression of CYP4F2 in primary human hepatocytes, and in SREBP-1a transfected HepG2 cells SREBP-1a was found to mediate lovastatin-induced expression of CYP4F2 [Article:17142457]. None of these findings have been confirmed in clinical studies, although a few case studies provide some evidence that co-administration of lovastatin and warfarin is associated with longer prothrombin time in patients [Article:14998226].

Peroxisomal proliferators, such as clofibrate, WY14,643, and PDFO, were shown to inhibit CYP4F2 gene expression [Articles:10860554, 17142457]. The anti-fungal drug ketoconazole and sesamin, a molecule found in sesame oil, also inhibit ω-hydroxylation of tocopherols in rat and human liver microsomes, as well as in HepG2 cells. Studies with recombinant CYP4F2 expressed in insect cells demonstrated that CYP4F2 is enzymatically inhibited by both ketoconazole and sesamin [Articles:15753130, 11997390, 11061988].

Genetic variants of CYP4F2
Initially investigated due to its role in eicosanoid metabolism, rs2108622 was later discovered to have a small, albeit significant, role in affecting warfarin dose in several populations, most notably in Han Chinese and several different White populations. The rs2108622 (NT_011295.11:g.7253233C>T, V433M) polymorphism was initially reported in a screen of CYP4F2 in an effort to discover SNPs associated with alterations in AA metabolism [Article:17341693]. The T allele at rs2108622 is also associated with increased blood pressure [Articles:24984178, 18391101] and decreased vitamin E metabolism [Articles:20861217, 21729881].

A study in Han Chinese reported that a seven SNP haplotype (Haplotype I) in the proximal regulatory region of CYP4F2 that included the A allele at rs3093105 (NC_000019.10:g.15897578A>C, W12G) was associated with increased urinary 20-HETE and increased risk of hypertension in case-control studies. Haplotype I was also transmitted more frequently to hypertensive offspring in family association studies [Article:18235092]. In vitro assays showed that Haplotype I was associated with increased basal, as well as LPS-induced expression of CYP4F2 when compared to Haplotype II, which included the C allele at rs3093105. Sequence analysis and functional studies showed that a second SNP in Haplotype II, rs3093098 (NC_000019.10:g.15897702A>G), eliminated a putative nuclear factor κB binding site, which provides a plausible explanation for the decrease in basal and LPS-induced expression associated with Haplotype II as compared to Haplotype I. A separate study in Japanese patients reported that when it is part of a haplotype with two other SNPS (rs1558139 A and rs2108622 C) the A allele at rs3093105 was protective against hypertension in men [Article:18971550].

Citation PharmGKB summary: very important pharmacogene information for CYP4F2. Pharmacogenetics and genomics. 2014. Alvarellos Maria L, Sangkuhl Katrin, Daneshjou Roxana, Whirl-Carrillo Michelle, Altman Russ B, Klein Teri E. PubMed
History

Submitted by Maria Alvarellos

Key Publications
  1. Genetic Risk Factors for Major Bleeding in Warfarin Patients in a Community Setting. Clinical pharmacology and therapeutics. 2014. Roth Joshua A, Boudreau Denise, Fujii Monica M, Farin Federico M, Rettie Allan E, Thummel Kenneth E, Veenstra David L. PubMed
  2. Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis. Clinical pharmacology and therapeutics. 2012. Danese E, Montagnana M, Johnson J A, Rettie A E, Zambon C F, Lubitz S A, Suarez-Kurtz G, Cavallari L H, Zhao L, Huang M, Nakamura Y, Mushiroda T, Kringen M K, Borgiani P, Ciccacci C, Au N T, Langaee T, Siguret V, Loriot M A, Sagreiya H, Altman R B, Shahin M H A, Scott S A, Khalifa S I, Chowbay B, Suriapranata I M, Teichert M, Stricker B H, Taljaard M, Botton M R, Zhang J E, Pirmohamed M, Zhang X, Carlquist J F, Horne B D, Lee M T M, Pengo V, Guidi G C, Minuz P, Fava C. PubMed
  3. CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant. Molecular pharmacology. 2009. McDonald Matthew G, Rieder Mark J, Nakano Mariko, Hsia Clara K, Rettie Allan E. PubMed
  4. CYP4F2 genetic variant alters required warfarin dose. Blood. 2008. Caldwell Michael D, Awad Tarif, Johnson Julie A, Gage Brian F, Falkowski Mat, Gardina Paul, Hubbard Jason, Turpaz Yaron, Langaee Taimour Y, Eby Charles, King Cristi R, Brower Amy, Schmelzer John R, Glurich Ingrid, Vidaillet Humberto J, Yale Steven H, Qi Zhang Kai, Berg Richard L, Burmester James K. PubMed
  5. Human enteric microsomal CYP4F enzymes O-demethylate the antiparasitic prodrug pafuramidine. Drug metabolism and disposition: the biological fate of chemicals. 2007. Wang Michael Zhuo, Wu Judy Qiju, Bridges Arlene S, Zeldin Darryl C, Kornbluth Sally, Tidwell Richard R, Hall James Edwin, Paine Mary F. PubMed
  6. Functional polymorphism in human CYP4F2 decreases 20-HETE production. Physiological genomics. 2007. Stec David E, Roman Richard J, Flasch Averia, Rieder Mark J. PubMed
  7. Regulation of human cytochrome P450 4F2 expression by sterol regulatory element-binding protein and lovastatin. The Journal of biological chemistry. 2007. Hsu Mei-Hui, Savas Uzen, Griffin Keith J, Johnson Eric F. PubMed
  8. CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime]. Drug metabolism and disposition: the biological fate of chemicals. 2006. Wang Michael Zhuo, Saulter Janelle Y, Usuki Etsuko, Cheung Yen-Ling, Hall Michael, Bridges Arlene S, Loewen Greg, Parkinson Oliver T, Stephens Chad E, Allen James L, Zeldin Darryl C, Boykin David W, Tidwell Richard R, Parkinson Andrew, Paine Mary F, Hall James Edwin. PubMed
  9. Discovery, characterization, and significance of the cytochrome P450 omega-hydroxylase pathway of vitamin E catabolism. Annals of the New York Academy of Sciences. 2004. Parker Robert S, Sontag Timothy J, Swanson Joy E, McCormick Charles C. PubMed
  10. Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriuretic eicosanoid, in human kidney. Role of Cyp4F2 and Cyp4A11. The Journal of biological chemistry. 2000. Lasker J M, Chen W B, Wolf I, Bloswick B P, Wilson P D, Powell P K. PubMed
Variant Summaries rs2108622
Drugs
Drug Inhibitor (2)
Drug Inducer (1)
Diseases
Pathways
Phenotypes Vitamin K Blood Pressure

Haplotype Overview

Haplotypes are derived from the Human Cytochrome P450 (CYP) Allele Nomenclature Database; 3/10/2014.

Source: PharmGKB

All alleles in the download file are on the positive chromosomal strand. PharmGKB considers the first haplotype listed in each table as the reference haplotype for that set.

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. Warfarin Pathway, Pharmacodynamics
    Simplified diagram of the target of warfarin action and downstream genes and effects.

Curated Information ?

Evidence Gene
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
APOE
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
CYP2C9
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
GGCX
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
VKORC1

Curated Information ?

Curated Information ?

Publications related to CYP4F2: 126

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic variants associated with warfarin dosage in Kuwaiti population. Pharmacogenomics. 2017. John Sumi Elsa, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
The impact of non-genetic and genetic factors on a stable warfarin dose in Thai patients. European journal of clinical pharmacology. 2017. Wattanachai Nitsupa, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
The association between GGCX, miR-133 genetic polymorphisms and warfarin stable dosage in Han Chinese patients with mechanical heart valve replacement. Journal of clinical pharmacy and therapeutics. 2017. Tang X-Y, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement. Medicine. 2017. Liu Rui, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic polymorphisms of patients on stable warfarin maintenance therapy in a Ghanaian population. BMC research notes. 2016. Kudzi William, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Landscape of warfarin and clopidogrel pharmacogenetic variants in Qatari population from whole exome datasets. Pharmacogenomics. 2016. Sivadas Ambily, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic determinants of variability in warfarin response after the dose-titration phase. Pharmacogenetics and genomics. 2016. Iwuchukwu Otito F, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Influence of genetic polymorphisms in cytochrome P450 oxidoreductase on the variability in stable warfarin maintenance dose in Han Chinese. European journal of clinical pharmacology. 2016. Zeng Wu-Tao, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy. Pharmacogenomics. 2016. Eriksson Niclas, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Exploring Variation in Known Pharmacogenetic Variants and its Association with Drug Response in Different Mexican Populations. Pharmaceutical research. 2016. Gonzalez-Covarrubias Vanessa, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Effect of VKORC1, CYP2C9, CFP4F2, and GGCX Gene Polymorphisms on Warfarin Dose in Japanese Pediatric Patients. Molecular diagnosis & therapy. 2016. Wakamiya Takuya, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose: A systematic review and meta-analysis. Biomedical reports. 2016. Sun Xue, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
An expanded pharmacogenomics warfarin dosing table with utility in generalised dosing guidance. Thrombosis and haemostasis. 2016. Shahabi Payman, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Race-specific influence of CYP4F2 on dose and risk of hemorrhage among warfarin users. Pharmacotherapy. 2016. Shendre Aditi, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Influence of UDP-Glucuronosyltransferase Polymorphisms on Stable Warfarin Doses in Patients with Mechanical Cardiac Valves. Cardiovascular therapeutics. 2015. An Sook Hee, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A multi-factorial analysis of response to warfarin in a UK prospective cohort. Genome medicine. 2016. Bourgeois Stephane, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
A New Pharmacogenetic Algorithm to Predict the Most Appropriate Dosage of Acenocoumarol for Stable Anticoagulation in a Mixed Spanish Population. PloS one. 2016. Tong Hoi Y, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics. PloS one. 2016. Duconge Jorge, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Effect of CYP2C9, VKORC1, and CYP4F2 polymorphisms on warfarin maintenance dose in children aged less than 18 years: a protocol for systematic review and meta-analysis. Systematic reviews. 2016. Takeuchi Masanobu, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genotype-guided therapy improves initial acenocoumarol dosing. Results from a prospective randomised study. Thrombosis and haemostasis. 2015. Cerezo-Manchado Juan Jose, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effects of NAD(P)H quinone oxidoreductase 1 polymorphisms on stable warfarin doses in Korean patients with mechanical cardiac valves. European journal of clinical pharmacology. 2015. Chung Jee-Eun, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Race influences warfarin dose changes associated with genetic factors. Blood. 2015. Limdi Nita A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX. Pharmacogenetics and genomics. 2015. Fohner Alison E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetics-based warfarin dosing algorithm decreases time to stable anticoagulation and the risk of major hemorrhage: an updated meta-analysis of randomized controlled trials. Journal of cardiovascular pharmacology. 2015. Wang Zhi-Quan, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Alcohol misuse, genetics, and major bleeding among warfarin therapy patients in a community setting. Pharmacoepidemiology and drug safety. 2015. Roth Joshua A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Clinical benefits of pharmacogenetic algorithm-based warfarin dosing: meta-analysis of randomized controlled trials. Thrombosis research. 2015. Li Xiaoqi, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of clinical factors and gene polymorphism of CYP2C19*2, *17 and CYP4F2*3 on early stent thrombosis. Pharmacogenomics. 2015. Kupstyte Nora, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population. European journal of clinical pharmacology. 2015. Krishna Kumar Dhakchinamoorthi, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genotype and risk of major bleeding during warfarin treatment. Pharmacogenomics. 2014. Kawai Vivian K, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
A Randomized Trial of Pharmacogenetic Warfarin Dosing in Naïve Patients with Non-Valvular Atrial Fibrillation. PloS one. 2015. Pengo Vittorio, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Warfarin dosage response related pharmacogenetics in chinese population. PloS one. 2015. Li Siyue, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
PharmGKB summary: very important pharmacogene information for CYP4F2. Pharmacogenetics and genomics. 2014. Alvarellos Maria L, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Prediction of stable acenocoumarol dose by a pharmacogenetic algorithm. Pharmacogenetics and genomics. 2014. Jiménez-Varo Enrique, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Characterizing variability in warfarin dose requirements in children using modelling and simulation. British journal of clinical pharmacology. 2014. Hamberg Anna-Karin, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic epidemiology of pharmacogenetic variations in CYP2C9, CYP4F2 and VKORC1 genes associated with warfarin dosage in the Indian population. Pharmacogenomics. 2014. Giri Anil K, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic determinants of acenocoumarol and warfarin maintenance dose requirements in Slavic population: A potential role of CYP4F2 and GGCX polymorphisms. Thrombosis research. 2014. Wypasek Ewa, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
The role of clinical parameters and of CYP2C19 G681 and CYP4F2 G1347A polymorphisms on platelet reactivity during dual antiplatelet therapy. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. 2014. Tatarunas Vacis, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
The impact of age and CYP2C9 and VKORC1 variants on stable warfarin dose in the paediatric population. British journal of haematology. 2014. Vear Susan I, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. Pediatric blood & cancer. 2014. Shaw Kaitlyn, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Methodological issues in the development of a pharmacogenomic algorithm for warfarin dosing: comparison of two regression approaches. Pharmacogenomics. 2014. Pavani Addepalli, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of VKORC1, CYP2C9 and CYP4F2 genetic variants in early outcomes during acenocoumarol treatment. Pharmacogenomics. 2014. Cerezo-Manchado Juan Jose, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetic-guided dosing of coumarin anticoagulants: algorithms for warfarin, acenocoumarol and phenprocoumon. British journal of clinical pharmacology. 2014. Verhoef Talitha I, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
CYP2C9, VKORC1, CYP4F2, ABCB1 and F5 variants: influence on quality of long-term anticoagulation. Pharmacological reports : PR. 2014. Nahar Risha, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
CYP4F2 1347 G > A & GGCX 12970 C > G polymorphisms: frequency in north Indians & their effect on dosing of acenocoumarol oral anticoagulant. The Indian journal of medical research. 2014. Rathore Saurabh Singh, et al. PubMed
Genetic Risk Factors for Major Bleeding in Warfarin Patients in a Community Setting. Clinical pharmacology and therapeutics. 2014. Roth Joshua A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of CYP2C9, VKORC1, CYP4F2 and GGCX genetic variants on warfarin maintenance dose and explicating a new pharmacogenetic algorithm in South Indian population. European journal of clinical pharmacology. 2014. Krishna Kumar Dhakchinamoorthi, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A pharmacogenetics-based warfarin maintenance dosing algorithm from northern chinese patients. PloS one. 2014. Chen Jinxing, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic Polymorphism of Cytochrome P450 4F2, Vitamin E Level and Histological Response in Adults and Children with Nonalcoholic Fatty Liver Disease Who Participated in PIVENS and TONIC Clinical Trials. PloS one. 2014. Athinarayanan Shaminie, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Cytochrome P450-dependent catabolism of vitamin K: ω-hydroxylation catalyzed by human CYP4F2 and CYP4F11. Biochemistry. 2013. Edson Katheryne Z, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Cytochrome P450 oxidoreductase genetic polymorphisms A503V and rs2868177 do not significantly affect warfarin stable dosage in Han-Chinese patients with mechanical heart valve replacement. European journal of clinical pharmacology. 2013. Tan Sheng-Lan, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Impact of genotype-guided dosing on anticoagulation visits for adults starting warfarin: a randomized controlled trial. Pharmacogenomics. 2013. Jonas Daniel E, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Warfarin pharmacogenetics: a controlled dose-response study in healthy subjects. Vascular medicine (London, England). 2013. Kadian-Dodov Daniella L, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
PS3-4: Genetic Risk Factors for Major Bleeding in Warfarin Patients in a Community Setting. Clinical medicine & research. 2013. Roth Joshua, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children. Pediatric blood & cancer. 2013. Visscher H, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Impact of Genetic Factors (CYP2C9, VKORC1 and CYP4F2) on Warfarin Dose Requirement in the Turkish Population. Basic & clinical pharmacology & toxicology. 2013. Ozer Mahmut, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population. European journal of clinical pharmacology. 2013. Rusdiana T, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Evaluation of the effect of SNPs in CYP3A4 and CYP4F2 on the stable phenprocoumon and acenocoumarol maintenance dose. Journal of thrombosis and haemostasis : JTH. 2013. van Schie Rianne M F, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pathway analysis of genome-wide data improves warfarin dose prediction. BMC genomics. 2013. Daneshjou Roxana, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Influence of CYP4F2 polymorphisms and plasma vitamin K levels on warfarin sensitivity in Japanese pediatric patients. Drug metabolism and pharmacokinetics. 2013. Hirai Keita, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin. International journal of hematology. 2012. Ma Cong, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans. Pharmacogenomics. 2012. Bress Adam, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenetics and cardiovascular disease--implications for personalized medicine. Pharmacological reviews. 2013. Johnson Julie A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Warfarin anticoagulant therapy: a southern Italy pharmacogenetics-based dosing model. PloS one. 2013. Mazzaccara Cristina, et al. PubMed
Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis. Clinical pharmacology and therapeutics. 2012. Danese E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenomics in clinical practice and drug development. Nature biotechnology. 2012. Harper Andrew R, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Influence of genetics and non-genetic factors on acenocoumarol maintenance dose requirement in Moroccan patients. Journal of clinical pharmacy and therapeutics. 2012. Smires F Z, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
CYP4F2 gene polymorphism as a contributor to warfarin maintenance dose in Japanese subjects. Journal of clinical pharmacy and therapeutics. 2012. Nakamura K, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effect of the VKORC1 D36Y variant on warfarin dose requirement and pharmacogenetic dose prediction. Thrombosis and haemostasis. 2012. Kurnik D, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Impact of CYP2C9*3, VKORC1-1639, CYP4F2rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients. Journal of thrombosis and thrombolysis. 2012. Liang Ruijuan, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Influence of CYP4F2 genotype on warfarin dose requirement-a systematic review and meta-analysis. Thrombosis research. 2012. Liang Ruijuan, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Retrospective evidence for clinical validity of expanded genetic model in warfarin dose optimization in a South Indian population. Pharmacogenomics. 2012. Pavani Addepalli, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effects of CYP4F2 gene polymorphisms on warfarin clearance and sensitivity in Korean patients with mechanical cardiac valves. Therapeutic drug monitoring. 2012. Lee Kyung-Eun, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A new algorithm to predict warfarin dose from polymorphisms of CYP4F2 , CYP2C9 and VKORC1 and clinical variables: derivation in Han Chinese patients with non valvular atrial fibrillation. Thrombosis and haemostasis. 2012. Wei Meng, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effects of CYP4F2 polymorphism on response to warfarin during induction phase: a prospective, open-label, observational cohort study. Clinical therapeutics. 2012. Bejarano-Achache Idit, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Impact of genetic factors (VKORC1, CYP2C9, CYP4F2 and EPHX1) on the anticoagulation response to fluindione. British journal of clinical pharmacology. 2012. Lacut Karine, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Predicting warfarin dosage in European-Americans and African-Americans using DNA samples linked to an electronic health record. Pharmacogenomics. 2012. Ramirez Andrea H, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children. Blood. 2012. Biss Tina T, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement. Blood. 2012. Moreau Caroline, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Copy number variation and warfarin dosing: evaluation of CYP2C9, VKORC1, CYP4F2, GGCX and CALU. Pharmacogenomics. 2011. Scott Stuart A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
An acenocoumarol dosing algorithm using clinical and pharmacogenetic data in spanish patients with thromboembolic disease. PloS one. 2012. Borobia Alberto M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Therapeutic dosing of acenocoumarol: proposal of a population specific pharmacogenetic dosing algorithm and its validation in north Indians. PloS one. 2012. Rathore Saurabh Singh, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genome-wide association study identifies common variants associated with circulating vitamin E levels. Human molecular genetics. 2011. Major Jacqueline M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Pharmacogenomic Prediction of Anthracycline-Induced Cardiotoxicity in Children. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011. Visscher Henk, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Association of apolipoprotein E genotype with duration of time to achieve a stable warfarin dose in African-American patients. Pharmacotherapy. 2011. Cavallari Larisa H, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy. Blood. 2011. Gong Inna Y, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenomics: the genetics of variable drug responses. Circulation. 2011. Roden Dan M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters. European journal of clinical pharmacology. 2011. Geisen Christof, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients. Journal of human genetics. 2011. Choi Jung Ran, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genomics and drug response. The New England journal of medicine. 2011. Wang Liewei, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Translational aspects of genetic factors in the prediction of drug response variability: a case study of warfarin pharmacogenomics in a multi-ethnic cohort from Asia. The pharmacogenomics journal. 2011. Chan S L, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic warfarin dosing tables versus algorithms. Journal of the American College of Cardiology. 2011. Finkelman Brian S, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Dependency of phenprocoumon dosage on polymorphisms in the VKORC1, CYP2C9, and CYP4F2 genes. Pharmacogenetics and genomics. 2011. Teichert Martina, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic and nongenetic factors associated with warfarin doserequirements in Egyptian patients. Pharmacogenetics and genomics. 2011. Shahin Mohamed Hossam A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Influence of CYP4F2 rs2108622 (V433M) on warfarin dose requirement in Asian patients. Drug metabolism and pharmacokinetics. 2011. Singh Onkar, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. Human molecular genetics. 2010. Cha Pei-Chieng, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction. Journal of biomedicine & biotechnology. 2011. Kringen Marianne K, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Clinical and Genetic Determinants of Warfarin Pharmacokinetics and Pharmacodynamics during Treatment Initiation. PloS one. 2011. Gong Inna Y, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Characterization of 107 genomic DNA reference materials for CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1: a GeT-RM and Association for Molecular Pathology collaborative project. The Journal of molecular diagnostics : JMD. 2010. Pratt Victoria M, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Common variants of cytochrome P450 4F2 exhibit altered vitamin E-{omega}-hydroxylase specific activity. The Journal of nutrition. 2010. Bardowell Sabrina A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements. Journal of human genetics. 2010. Ross Kendra A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
CYP4F2 rs2108622: a minor significant genetic factor of warfarin dose in Han Chinese patients with mechanical heart valve replacement. British journal of clinical pharmacology. 2010. Cen Han-Jing, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9. Pharmacogenetics and genomics. 2010. Sagreiya Hersh, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Combined CYP2C9, VKORC1 and CYP4F2 frequencies among racial and ethnic groups. Pharmacogenomics. 2010. Scott Stuart A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A regression model to predict warfarin dose from clinical variables and polymorphisms in CYP2C9, CYP4F2, and VKORC1: Derivation in a sample with predominantly a history of venous thromboembolism. Thrombosis research. 2010. Wells P S, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population. Journal of thrombosis and haemostasis : JTH. 2010. Lubitz S A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Clinical assessment incorporating a personal genome. Lancet. 2010. Ashley Euan A, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic and clinical predictors of warfarin dose requirements in African Americans. Clinical pharmacology and therapeutics. 2010. Cavallari L H, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Impact of CYP4F2 rs2108622 on the stable warfarin dose in an admixed patient cohort. Clinical pharmacology and therapeutics. 2010. Perini J A, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Association of common variants of CYP4A11 and CYP4F2 with stroke in the Han Chinese population. Pharmacogenetics and genomics. 2010. Ding Hu, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Genetic factors (VKORC1, CYP2C9, EPHX1, and CYP4F2) are predictor variables for warfarin response in very elderly, frail inpatients. Clinical pharmacology and therapeutics. 2010. Pautas E, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
VKORC1, CYP2C9 and CYP4F2 genetic-based algorithm for warfarin dosing: an Italian retrospective study. Pharmacogenomics. 2010. Zambon Carlo-Federico, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Pharmacogenomics: role in medicines approval and clinical use. Public health genomics. 2010. Novelli G, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A genome-wide association study of acenocoumarol maintenance dosage. Human molecular genetics. 2009. Teichert Martina, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Effects of CYP4F2 genetic polymorphisms and haplotypes on clinical outcomes in patients initiated on warfarin therapy. Pharmacogenetics and genomics. 2009. Zhang Jieying Eunice, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Generating genome-scale candidate gene lists for pharmacogenomics. Clinical pharmacology and therapeutics. 2009. Hansen N T, et al. PubMed
CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant. Molecular pharmacology. 2009. McDonald Matthew G, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Pharmacogenetic relevance of CYP4F2 V433M polymorphism on acenocoumarol therapy. Blood. 2009. Pérez-Andreu Virginia, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS genetics. 2009. Takeuchi Fumihiko, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. Pharmacogenomics. 2009. Borgiani Paola, et al. PubMed
CYP4F2 genetic variant alters required warfarin dose. Blood. 2008. Caldwell Michael D, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Human enteric microsomal CYP4F enzymes O-demethylate the antiparasitic prodrug pafuramidine. Drug metabolism and disposition: the biological fate of chemicals. 2007. Wang Michael Zhuo, et al. PubMed
Functional polymorphism in human CYP4F2 decreases 20-HETE production. Physiological genomics. 2007. Stec David E, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Regulation of human cytochrome P450 4F2 expression by sterol regulatory element-binding protein and lovastatin. The Journal of biological chemistry. 2007. Hsu Mei-Hui, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
CYP4F enzymes are the major enzymes in human liver microsomes that catalyze the O-demethylation of the antiparasitic prodrug DB289 [2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime]. Drug metabolism and disposition: the biological fate of chemicals. 2006. Wang Michael Zhuo, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Discovery, characterization, and significance of the cytochrome P450 omega-hydroxylase pathway of vitamin E catabolism. Annals of the New York Academy of Sciences. 2004. Parker Robert S, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
Formation of 20-hydroxyeicosatetraenoic acid, a vasoactive and natriuretic eicosanoid, in human kidney. Role of Cyp4F2 and Cyp4A11. The Journal of biological chemistry. 2000. Lasker J M, et al. PubMed

LinkOuts

NCBI Gene:
8529
OMIM:
604426
UCSC Genome Browser:
NM_001082
RefSeq RNA:
NM_001082
RefSeq Protein:
NP_001073
RefSeq DNA:
NG_007971
NT_011295
UniProtKB:
CP4F2_HUMAN (P78329)
Ensembl:
ENSG00000186115
GenAtlas:
CYP4F2
GeneCard:
CYP4F2
MutDB:
CYP4F2
ALFRED:
LO006390S
HuGE:
CYP4F2
Comparative Toxicogenomics Database:
8529
ModBase:
P78329
HumanCyc Gene:
HS02675
HGNC:
2645

Common Searches