|(A;A)||0.1||normal; no effect on warfarin metabolism|
|(A;C)||2.5||CYP2C9*3 carrier; average 40% reduction in warfarin metabolism|
|(C;C)||4||CYP2C9*3 homozygote; average 80% reduction in warfarin metabolism; reduced metabolism of number of other drugs|
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SNP rs1057910(A), located in the cytochrome p450 CYP2C9 gene, most commonly encodes the amino acid isoleucine at position 359, and the resulting allele is also known as CYP2C9*1. rs1057910(C) encodes a leucine at this same position, and the resulting allele is called CYP2C9*3. This SNP is also known as Ile359Leu or A1075C.
The effect of CYP2C9 variants on drug metabolism should not be predicted without also considering CYP2C9*2, defined as the common loss of function variant rs1799853(T) (NM_000771:c.430C>T, NP_000762:p.144R>C) [PMID 8004131] .
Studies of the effects of these alleles include:
- rs1057910(C;C) genotypes may clear drugs like celecoxib (trade name Celebrex) twice as slowly as rs1057910(A;A) genotypes; the rs1057910(A;C) genotypes are in-between clearance rates. Lower clearance rates will lead to higher internal concentrations of the drug. It is not clear whether this could lead to increased efficacy and/or increased side effects. [PMID 12893985]
- rs1057910(C;C) genotypes are poor metabolizers of tolbutamide, a sulfonylurea hypoglycemic drug used in the treatment of diabetes. [PMID 8873220]
- rs1057910(C;C) genotypes are poor metabolizers of phenytoin, a drug used to treat epilepsy, and therefore tend to need lower doses. [PMID 15805193] Note however that the CPIC (and FDA) recommend testing for the HLA-B*15:02 allele, since carriers are at significantly increased risk of Stevens-Johnson syndrome (SJS/PTEN).
- rs1057910(C;C) genotypes are poor metabolizers of glipizide, a second generation sulfonylurea drug structurally similar to tolbutamide and also used as an oral hypoglycemic agent. [PMID 10208645]
- rs1057910(C;C) genotypes are poor metabolizers of warfarin, and therefore unusually sensitive. [PMID 9352571]
- See also OMIM 601130.0001
Individuals carrying this SNP may show increased risk of developing acute gastrointestinal bleeding during the use of NSAIDs that are CYP2C8 or CYP2C9 substrates, such as aceclofenac, celecoxib, diclofenac, ibuprofen, indomethazine, lornoxicam, meloxicam, naproxen, piroxicam, tenoxicam and valdecoxib.[PMID 19422321]
|Trait||Warfarin maintenance dose|
|Title||A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose|
|Odds Ratio||1.11 [1.00-1.22] mg/week decrease|
[PMID 20214591] Pharmacogenomics in aspirin intolerance
[PMID 20555338] Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements
[PMID 20842355] VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China
[PMID 22321278] [Impact of CYP2C9 and VKORC1 polymorphism on warfarin response during initiation of therapy]
[PMID 16385451] A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.
[PMID 17048007] Association of warfarin dose with genes involved in its action and metabolism.
[PMID 17368604] The association of CYP2C9 gene polymorphisms with colorectal carcinoma in Han Chinese.
[PMID 17387222] Genetic-based dosing in orthopedic patients beginning warfarin therapy.
[PMID 18305455] Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin.
[PMID 18466099] Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans.
[PMID 18547414] Genotyping panel for assessing response to cancer chemotherapy.
[PMID 18574025] The largest prospective warfarin-treated cohort supports genetic forecasting.
[PMID 18596683] Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans.
[PMID 18662264] Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients.
[PMID 18680736] Genetic factors contribute to patient-specific warfarin dose for Han Chinese.
[PMID 18752379] Warfarin pharmacogenetics.
[PMID 18936436] Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994.
[PMID 18990750] Red meat intake, doneness, polymorphisms in genes that encode carcinogen-metabolizing enzymes, and colorectal cancer risk.
[PMID 18992263] Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways.
[PMID 19223558] Polymorphic variation in NFKB1 and other aspirin-related genes and risk of Hodgkin lymphoma.
[PMID 19538716] Thrombotic genetic risk factors and warfarin pharmacogenetic variants in Sao Miguel's healthy population (Azores).
[PMID 19694740] No significant effect of ABCB1 haplotypes on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin.
[PMID 19955245] Warfarin sensitivity genotyping: a review of the literature and summary of patient experience.
[PMID 20017677] ARMS test for diagnosis of CYP2C9 and VKORC1 mutation in patients with pulmonary embolism in Han Chinese.
[PMID 20082485] Genetic variants involved in gallstone formation and capsaicin metabolism, and the risk of gallbladder cancer in Chilean women.
[PMID 20149073] Pharmacogenetics of acenocoumarol in patients with extreme dose requirements.
[PMID 20459744] Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study.
[PMID 20585445] A novel, single algorithm approach to predict acenocoumarol dose based on CYP2C9 and VKORC1 allele variants.
[PMID 20733952] Warfarin genotyping using three different platforms.
[PMID 20808793] Are cytochrome P450 CYP2C8 and CYP2C9 polymorphisms associated with ibuprofen response in very preterm infants?
[PMID 22010099] VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children.
[PMID 22178823] [Distribution of variant alleles association with warfarin pharmacokinetics and pharmacodynamics in the Han population in China].
[PMID 22486182] Influence of genetics and non-genetic factors on acenocoumarol maintenance dose requirement in Moroccan patients.
[PMID 22569204] PharmGKB summary: phenytoin pathway.
[PMID 23081681] CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment
[PMID 23208322] Influence of ORM1 polymorphisms on the maintenance stable warfarin dosage
[PMID 23473641] Effect of CYP2C9 and VKORC1 genetic polymorphisms on mean daily maintenance dose of acenocoumarol in South Indian patients
[PMID 23104259] Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin
[PMID 23587916] Allele frequency distribution of CYP2C9 2 and CYP2C9 3 polymorphisms in six Mexican populations
[PMID 24324947] VKORC1 and CYP2C9 Genotype Variations in Relation to Warfarin Dosing in Korean Stroke Patients
[PMID 24368493] Interaction between ALOX5AP and CYP3A5 gene variants significantly increases the risk for cerebral infarctions in Chinese
[PMID 24380239] Characterization of the most common CYP2C9 and CYP2C19 allelic variants in the population from the Republic of Macedonia
[PMID 24602049] Association of gene polymorphisms with the risk of warfarin bleeding complications at therapeutic INR in patients with mechanical cardiac valves
[PMID 22676711] Pharmacogenomics of warfarin in populations of African descent.
[PMID 23089684] Similarity in recombination rate and linkage disequilibrium at CYP2C and CYP2D cytochrome P450 gene regions among Europeans indicates signs of selection and no advantage of using tagSNPs in population isolates.
[PMID 23130019] Frequencies of 23 functionally significant variant alleles related with metabolism of antineoplastic drugs in the chilean population: comparison with caucasian and asian populations.
[PMID 23133420] Pharmacogenomic Diversity among Brazilians: Influence of Ancestry, Self-Reported Color, and Geographical Origin.
[PMID 23691226] Novel associations of VKORC1 variants with higher acenocoumarol requirements.
[PMID 24966969] High resolution melting method to detect single nucleotide polymorphism of VKORC1 and CYP2C9
[PMID 23941071] Association of genetic polymorphisms with warfarin dose requirements in Chinese patients
[PMID 25069408] Multiplex pyrosequencing method to determine CYP2C9*3, VKORC1*2, and CYP4F2*3 polymorphisms simultaneously: its application to a Korean population and comparisons with other ethnic groups
[PMID 26265036] Genome-wide association study of warfarin maintenance dose in a Brazilian sample
[PMID 26402341] High allele frequency of CYP2C9*3 (rs1057910) in a Negrito's subtribe population in Malaysia; Aboriginal people of Jahai