Guidelines regarding the use of pharmacogenomic tests in dosing for warfarin have been published in Clinical Pharmacology and Therapeutics by the Clinical Pharmacogenetics Implementation Consortium (CPIC).
Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing.
Julie A. Johnson, Li Gong, Michelle Whirl-Carrillo, Brian F. Gage, Stuart A. Scott, C., Michael Stein, Jeffrey L. Anderson, Stephen E. Kimmel, Ming Ta Michael Lee, Munir Pirmohamed, Mia Wadelius, Teri E. Klein, and Russ B. Altman. Clinical Pharmacology & Therapeutics (2011) Oct;90(4):625-629.
Download: article and supplement
Pharmacogenetic algorithm-based warfarin dosing
Excerpt from the warfarin dosing guidelines:
Numerous studies have derived warfarin dosing algorithms that use both genetic and non-genetic factors to predict warfarin dose [Article:18305455, 19228618, 18574025]. Two algorithms perform well in estimating stable warfarin dose across different ethnic populations; [Article: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 [Article: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 [Article:18305455, 19228618]). The dosing algorithm published by the International Warfarin Pharmacogenetics Consortium is also online, at http://www.pharmgkb.org/do/serve?objId=PA162372936&objCls=Dataset#tabview=tab2. The two algorithms provide very similar dose recommendations.
Download: IWPC Pharmacogenetic Dosing Algorithm
Approach to pharmacogenetic-based warfarin dosing without access to dosing algorithms
Excerpt from the warfarin dosing guidelines:
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.
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.
Table 1: Recommended daily warfarin doses (mg/day) to achieve a therapeutic INR based on CYP2C9 and VKORC1 genotype using the warfarin product insert approved by the United States Food and Drug Administration:
| VKORC1 Genotype (-1639G>A, rs9923231) | CYP2C9*1/*1 | CYP2C9*1/*2 | CYP2C9*1/*3 | CYP2C9*2/*2 | CYP2C9*2/*3 | CYP2C9*3/*3 |
|---|---|---|---|---|---|---|
| GG | 5-7 | 5-7 | 3-4 | 3-4 | 3-4 | 0.5-2 |
| GA | 5-7 | 3-4 | 3-4 | 3-4 | 0.5-2 | 0.5-2 |
| AA | 3-4 | 3-4 | 0.5-2 | 0.5-2 | 0.5-2 | 0.5-2 |
Reproduced from updated warfarin (Coumadin®) product label.
Supplemental Table S1. Genotypes that constitute the * alleles for CYP2C9
| Allele | Constituted by genotypes at: | Amino acid changes | Enzymatic Activity |
|---|---|---|---|
| *1 | reference allele at all positions | Normal | |
| *2 | C>T at rs1799853 | R144C | Decreased |
| *3 | A>C at rs1057910 | I359L | Decreased |
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for acenocoumarol based on CYP2C9 genotype (PMID:21412232).
| Genotype | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| CYP2C9 *1/*2 | Check INR more frequently after initiating or discontinuing NSAIDs | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S) |
| CYP2C9 *2/*2 | Check INR more frequently after initiating or discontinuing NSAIDs | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S) |
| CYP2C9 *1/*3 | Check INR more frequently after initiating or discontinuing NSAIDs | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x10{^}9^/l; leucopenia > 3.0x10{^}9^/l; thrombocytopenia > 75x10{^}9^/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test. |
| CYP2C9 *2/*3 | Check INR more frequently after initiating or discontinuing NSAIDs | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S) |
| CYP2C9 *3/*3 | Check INR more frequently during dose titration and after initiating or discontinuing NSAIDs | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S) |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
- Please see attached PDF for detailed information about the evaluated studies: Acenocoumarol CYP2C9
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for glibenclamide based on CYP2C9 genotype (PMID:21412232). They conclude that there are no recommendations at this time.
| Genotype | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| CYP2C9 *1/*2 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *2/*2 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *1/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test. |
| CYP2C9 *2/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *3/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5 |
- *See Methods or PMID: 18253145 for definition of "moderate" quality.
- S: statistically significant difference.
| Genotype | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| CYP2C9 *1/*2 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *2/*2 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *1/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *2/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *3/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
- *See Methods or PMID: 18253145 for definition of "moderate" quality.
- S: statistically significant difference.
- NS: non-significant
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for glimepiride based on CYP2C9 genotype (PMID:21412232). They conclude that there are no recommendations at this time.
| Genotype | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| CYP2C9 *1/*2 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *2/*2 | None | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *1/*3 | None | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) |
| CYP2C9 *2/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea |
| CYP2C9 *3/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x109/l; leucopenia 1.0-2.0x109/l; thrombocytopenia 25-50x109/l; severe diarrhea |
- *See Methods or PMID: 18253145 for definition of "good" and "moderate" quality.
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for phenprocoumon based on CYP2C9 genotype (PMID:21412232).
| Genotype | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| CYP2C9 *1/*2 | None | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression |
| CYP2C9 *2/*2 | Check INR more frequently | Published controlled studies of good quality\* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression |
| CYP2C9 *1/*3 | None | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression |
| CYP2C9 *2/*3 | Check INR more frequently | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): death; arrhythmia; unanticipated myelosuppression |
| CYP2C9 *3/*3 | Check INR more frequently | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10{^}9^/l; leucopenia 1.0-2.0x10{^}9^/l; thrombocytopenia 25-50x10{^}9^/l; severe diarrhea |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
The Royal Dutch Pharmacists Association - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for phenytoin based on CYP2C9 genotype (PMID:21412232).
| Genotype | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| CYP2C9 *1/*2 | Standard loading dose. Reduce maintenance dose by 25%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation) | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S) |
| CYP2C9 *2/*2 | Standard loading dose. Reduce maintenance dose by 50%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation) | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S) |
| CYP2C9 *1/*3 | Standard loading dose. Reduce maintenance dose by 25%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation) | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10{^}9^/l; leucopenia 1.0-2.0x10{^}9^/l; thrombocytopenia 25-50x10{^}9^/l; severe diarrhea |
| CYP2C9 *2/*3 | Standard loading dose. Reduce maintenance dose by 50%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation) | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5Kinetic effect (S) |
| CYP2C9 *3/*3 | Standard loading dose. Reduce maintenance dose by 50%. Evaluate response and serum concentration after 7-10 days. Be alert to ADEs (e.g., ataxia, nystagmus, dysarthria, sedation) | Published controlled studies of good quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): long-standing discomfort (> 168 hr), permanent symptom or invalidating injury e.g. failure of prophylaxis of atrial fibrillation; venous thromboembolism; decreased effect of clopidogrel on inhibition of platelet aggregation; ADE resulting from increased bioavailability of phenytoin; INR > 6.0; neutropenia 0.5-1.0x10{^}9^/l; leucopenia 1.0-2.0x10{^}9^/l; thrombocytopenia 25-50x10{^}9^/l; severe diarrhea |
- *See Methods or PMID: 18253145 for definition of "good quality."
- S: statistically significant difference.
The Royal Dutch Association for the Advancement of Pharmacy - Pharmacogenetics Working Group has evaluated therapeutic dose recommendations for tolbutamide based on CYP2C9 genotype (PMID:21412232).They conclude that there are no recommendations at this time.
| Genotype | Therapeutic Dose Recommendation | Level of Evidence | Clinical Relevance |
|---|---|---|---|
| CYP2C9 *1/*2 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *2/*2 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *1/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (S): short-lived discomfort (< 48 hr) without permanent injury: e.g. reduced decrease in resting heart rate; reduction in exercise tachycardia; decreased pain relief from oxycodone; ADE resulting from increased bioavailability of atomoxetine (decreased appetite, insomnia, sleep disturbance etc); neutropenia > 1.5x109/l; leucopenia > 3.0x109/l; thrombocytopenia > 75x109/l; moderate diarrhea not affecting daily activities; reduced glucose increase following oral glucose tolerance test. |
| CYP2C9 *2/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Clinical effect (NS) Kinetic effect (NS) |
| CYP2C9 *3/*3 | None | Published controlled studies of moderate quality* relating to phenotyped and/or genotyped patients or healthy volunteers, and having relevant pharmacokinetic or clinical endpoints. | Minor clinical effect (S): QTc prolongation (<450 ms females, <470 ms males); INR increase < 4.5 |
- *See Methods or PMID: 18253145 for definition of "moderate" quality.
- S: statistically significant difference.
Information regarding PGx on FDA drug labels is derived from the FDA's Table of Pharmacogenomic Biomarkers in Drug Labels. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB
The FDA recommends, but does not require, genetic testing of patients from at-risk populations prior to initiating treatment with CELEBREX.
Excerpt from the CELEBREX drug label:
"Poor Metabolizers of CYP2C9 Substrates: Patients who are known or suspected to be poor CYP2C9 metabolizers based on previous history/experience with other CYP2C9 substrates (such as warfarin, phenytoin) should be administered celecoxib with caution. Consider starting treatment at half the lowest recommended dose in poor metabolizers. Consider using alternative management in JRA patients who are poor metabolizers..."
"Celecoxib metabolism is primarily mediated via CYP2C9...CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from 4 published reports that included a total of 8 subjects with the homozygous CYP2C9*3/*3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of celecoxib have not been evaluated in subjects with other CYP2C9 polymorphisms, such as *2, *5, *6, *9 and *11. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3% to 1.0% in various ethnic groups."
"Consider a dose reduction by 50% (or alternative management for JRA) in patients who are known or suspected to be CYP2C9 poor metabolizers."
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the Celecoxib drug label.
*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.
The FDA recommends genetic testing prior to initiating treatment with warfarin.
Excerpt from the warfarin drug label:
The patient's CYP2C9 and VKORC1 genotype information, when available, can assist in selection of the starting dose. Table 5 describes the range of stable maintenance doses observed in multiple patients having different combinations of CYP2C9 and VKORC1 gene variants. Consider these ranges in choosing the initial dose.
The VKORC1:G-1639A polymorphism is associated with lower dose requirements for warfarin in Caucasian and Asian patients. Increased bleeding risk and lower initial warfarin dose requirements have been associated with the CYP2C9*2 and CYP2C9*3 alleles. Approximately 30% of the variance in warfarin dose could be attributed to genetic variation in VKORC1, and about 40% of dose variance could be explained taking into consideration both VKORC1 and CYP2C9 genetic polymorphisms. Accounting for genetic variation in both VKORC1 and CYP2C9, age, height, body weight, interacting drugs, and indication for warfarin therapy explained about 55% of the variability in warfarin dose.
For the complete drug label text with sections containing pharmacogenetic information highlighted, see the warfarin drug label. Pharmacogenomics-related dosing information is found in Table 5 on page 27.
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.
| Position ? | Drug ? | Relevance ? |
Strength of Evidence ? |
||
|---|---|---|---|---|---|
| rs1057910 | dose below average | 1 | |||
Download a summary of all Clinical Annotations available.
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.
A non-comprehensive list of genetic tests for specific variants, including descriptions of and links to individual tests; manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.
| PGx Test | Variants Assayed | Related Drugs? |
|---|---|---|
| TrimGen Corporation eQ-PCR LC Warfarin Genotyping Kit | CYP2C9*2, CYP2C9*3 |
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.
Links in the "Drugs" column lead to PharmGKB Drug Pages.
|
Variant?
(build 132) |
Alternate Names ? | Drugs ? | Alleles ? | Function ? |
Amino Acid?
Translation |
|
|---|---|---|---|---|---|---|
| rs1057910 | CYP2C9*3, CYP2C9*3:Ile359Leu, CYP2C9: I359L, CYP2C9:359Ile>Leu, CYP2C9:Ile359Leu, c.1075A>C, g.47545517A>C, g.47639A>C, g.96731043A>C, mRNA 11A>C, p.Ile359Leu | A > C | Missense | Ile359Leu | ||
| rs12782374 | A/G | Not Available | ||||
| rs1799853 | CYP2C9*2, CYP2C9:144Arg>Cys, CYP2C9:Arg144Cys, c.430C>T, g.47506511C>T, g.8633C>T, g.96692037C>T, mRNA 455C>T, p.Arg144Cys | C > T | Missense | Arg144Cys | ||
| rs28371685 | CYP2C9*11, CYP2C9:R335W, c.1003C>T, g.47545445C>T, g.47567C>T, p.Arg335Trp | C > T | Missense | Arg335Trp | ||
| rs28371686 | CYP2C9*5, CYP2C9:D360E, c.1080C>G, g.47545522C>G, p.Asp360Glu | C > G | Missense | Asp360Glu | ||
| rs4086116 | C/T | Intronic | ||||
| rs7089580 | A/T | Intronic | ||||
| rs71486745 | Not Available | |||||
| rs7900194 | CYP2C9*8, CYP2C9:R150H, c.449G>A, g.47506530G>A, g.8652G>A, p.Arg150His | G > A | Missense | Arg150His | ||
| rs9332131 | CYP2C9*6, CYP2C9:null allele, c.817delA, g.15625delA, g.47513503delA, p.Lys273fx | A | Frameshift | Lys | ||
| rs9332239 | c.1465C>T, g.47553241C>T, g.55363C>T, p.Pro489Ser | C > T | Missense | Pro489Ser |
Overview
| Alternate Names: | OTTHUMP00000020135; cytochrome P-450 S-mephenytoin 4-hydroxylase; cytochrome P-450MP; cytochrome P450 2C9; cytochrome P450 PB-1; cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 10; cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 9; cytochrome p4502C9; flavoprotein-linked monooxygenase; mephenytoin 4-hydroxylase; microsomal monooxygenase; xenobiotic monooxygenase |
|---|---|
| Alternate Symbols: | CPC9; CYP2C; CYP2C10; CYP2C9*1; CYP2C9*1A; CYPIIC9; MGC149605; MGC88320; P450 MP-4; P450 PB-1; P450IIC9 |
| Haplotypes: | CYP2C9*1; CYP2C9*2; CYP2C9*3; CYP2C9*4; CYP2C9*5; CYP2C9*6; CYP2C9*7; CYP2C9*8; CYP2C9*9; CYP2C9*10; CYP2C9*11; CYP2C9*12; CYP2C9*13; CYP2C9*14; CYP2C9*15; CYP2C9*16; CYP2C9*17; CYP2C9*18; CYP2C9*19; CYP2C9*20; CYP2C9*21; CYP2C9*22; CYP2C9*23; CYP2C9*24; CYP2C9*25; CYP2C9*26; CYP2C9*27; CYP2C9*28; CYP2C9*29; CYP2C9*30; CYP2C9*31; CYP2C9*32; CYP2C9*33; CYP2C9*34 |
| PharmGKB Accession Id: | PA126 |
Details
| Cytogenetic Location: | chr10 : q23.33 - q23.33 |
|---|---|
| GP mRNA Boundary†: | chr10 : 96698415 - 96749148 |
| GP Gene Boundary†: | chr10 : 96688415 - 96752148 |
| Strand: | plus |
| Product Name: | cytochrome P-450 S-mephenytoin 4-hydroxylase, cytochrome P450, family 2, subfamily C, polypeptide 9, cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 10, cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase), polypeptide 9, cytochrome p4502C9, flavoprotein-linked monooxygenase, mephenytoin 4-hydroxylase, microsomal monooxygenase, xenobiotic monooxygenase |
All alleles are displayed on the positive chromosomal strand.
| Haplotype | rs1057910 | rs1057911 | rs1799853 | rs2256871 | rs28371685 | rs28371686 | rs56165452 | rs57505750 | rs67807361 | rs72558184 | rs72558187 | rs72558188 | rs72558189 | rs72558190 | rs72558192 | rs72558193 | rs7900194 | rs9332130 | rs9332131 | rs9332239 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CYP2C9*1 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*2 | A | A | T | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*3 | C | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*4 | A | A | C | A | C | C | C | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*5 | A | A | C | A | C | G | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*6 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | del | C |
| CYP2C9*7 | A | A | C | A | C | C | T | C | A | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*8 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | A | A | A | C |
| CYP2C9*9 | A | A | C | G | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*10 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | G | A | C |
| CYP2C9*11 | A | A | C | A | T | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*12 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | T |
| CYP2C9*13 | A | A | C | A | C | C | T | C | C | G | C | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*14 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | A | C | A | A | G | A | A | C |
| CYP2C9*15 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | A | A | A | G | A | A | C |
| CYP2C9*16 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | G | A | G | A | A | C |
| CYP2C9*17 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*18 | C | T | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | C | G | A | A | C |
| CYP2C9*19 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*20 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*21 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*22 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*23 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*24 | A | A | C OR T | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*25 | A | A | C | A | C | C | T | C | C | G | T | del | G | C | A | A | G | A | A | C |
| CYP2C9*26 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*27 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*28 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*29 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*30 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*31 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*32 | A | A | C | A | C | C | T | C | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*33 | A | A | C | A | C | C | T | C | C | A | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
| CYP2C9*34 | A | A | C | A | C | C | T | T | C | G | T | AGAAATGGAA | G | C | A | A | G | A | A | C |
PharmGKB Curated Pathways
Pathways created internally by PharmGKB based primarily on literature evidence.
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Anti-diabetic Drug Nateglinide Pathway, Pharmacokinetics
Nateglinide metabolism and transport in liver cell.
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Atorvastatin/Lovastatin/Simvastatin Pathway, Pharmacokinetics
Drug-specific representation of the candidate genes involved in transport, metabolism and clearance.
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Caffeine Pathway, Pharmacokinetics
Stylized liver cell showing candidate genes involved in the metabolism of caffeine.
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Clopidogrel Pathway, Pharmacokinetics
Clopidogrel metabolism.
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Cyclophosphamide Pathway, Pharmacokinetics
Model human liver cell showing genes involved in the metabolism of cyclophosphamide.
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Fluoxetine Pathway, Pharmacokinetics
Representation of the candidate genes involved in the metabolism of fluoxetine.
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Fluvastatin Pathway, Pharmacokinetics
Drug-specific representation of the candidate genes involved in transport, metabolism and clearance.
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Gefitinib Pathway (PK)
Representation of the candidate genes involved in the transportation and metabolism of gefitinib
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Ifosfamide Pathway (PK)
Model human liver cell showing genes involved in the metabolism of ifosfamide
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Losartan Pathway, Pharmacokinetics
Representation of the candidate genes involved in the metabolism of losartan.
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Phenytoin Pathway, Pharmacokinetics
Genes involved in the metabolism of phenytoin in the human liver cell.
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Rosiglitazone Pharmacokinetic Pathway
Rosiglitazone is transported from hepatic sinusoids into hepatocytes -- a process mediated by the organic anion transporting polypeptide, where is is metabolized by cytochrome p450 2C8 and 2C9.
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Statin Pathway - Generalized, Pharmacokinetics
Representation of the superset of all genes involved in the transport, metabolism and clearance of statin class drugs.
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Tamoxifen Pathway, Pharmacokinetics
Tamoxifen metabolism in the liver.
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Warfarin Pathway, Pharmacokinetics
Representation of the candidate genes involved in transport, metabolism and clearance of warfarin.
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Zidovudine Pathway, Pharmacokinetics/Pharmacodynamics
Representation of candidate genes involved in the metabolism of zidovudine and its mechanism of antiviral action.
External Pathways
Links to non-PharmGKB pathways.
Datasets
- Bone mineral density in tamoxifen patients
- CYP2C9 Variants and Flurbiprofen Metabolism
- CYP2C9 Variants and Naproxen Metabolism
- CYP2C9 Variants and Piroxicam Metabolism
- Effects of Dapsone on CYP2C9 Variants and Flurbiprofen Metabolism
- Effects of Dapsone on CYP2C9 Variants and Naproxen Metabolism
- Hot flashes in tamoxifen patients
- IWPC Ethnicity Data Set, 2009
- IWPC Warfarin Data Set (NEJM 2009)
- Lipid measurements in tamoxifen study - set 2
- Meperidine N-demethylation by human CYP450 isoforms
- Patient responses to tamoxifen
- Pharmacokinetics of Tamoxifen at 4 months
- Thyroid binding globulin in tamoxifen patients
- Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin
- A chemogenomic approach to drug discovery: focus on cardiovascular diseases
- Genetic Determinants of Initial Warfarin Response
- Genetic Variants associated with Warfarin Response
- IWPC Pharmacogenetic Dosing Algorithm
- P450s involved in Efavirenz Metabolism
- Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin
Downloads
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LinkOuts
- Web Resource:
- http://www.imm.ki.se/CYPalleles/cyp2c9.htm
- UniProtKB:
- CP2C9_HUMAN (P11712)
- Q5VX92_HUMAN (Q5VX92)
- Ensembl:
- ENSG00000138109
- GenAtlas:
- CYP2C9
- GeneCard:
- GC10P096688 (1559)
- SOURCE:
- CYP2C9
Common Searches
Non-Curated Publications
A list of non-curated publications that mention this gene is available.