|(C;C)||1||normal; no risk of altered warfarin metabolism or NSAID metabolism|
|(C;T)||1.5||~20% reduction in warfarin metabolism; some NSAID risk|
|(T;T)||2||~ 40% reduction in warfarin metabolism, greater NSAID risk|
|Disease||Warfarin response warfarin response - Dosage not specified|
|CLNDBN||Warfarin response warfarin response - Dosage not specified|
|CLNSRC||OMIM Allelic Variant PharmGKB Clinical Annotation UniProtKB (protein)|
|CLNACC||RCV000150377.1, RCV000150378.1, RCV000008920.1, RCV000154312.1, RCV000211223.1, RCV000309101.1,|
rs1799853 is a SNP in the CYP2C9 gene and is linked to poor warfarin metabolism and risk of GI bleeding with some NSAID drugs.
The common nomenclature for this polymorphism is CYP2C9*2 (Cys amino acid, T allele; the SNP is also known as C430T or Cys144Arg).
[PMID 1305837] Advanced knowledge of this may influence initial warfarin dosing by physicians. Warfarin is monitored through INR (international normalized ratio) and proper dosing is influenced by a variety of factors including warfarin metabolism and diet.
The CYP2C9*2 allele is also associated with higher sensitivity to the anti-epileptic drug phenytoin. Note however that the CPIC (and FDA) mention concurrent testing for the HLA-B*15:02 allele, since carriers are at significantly increased risk of Stevens-Johnson syndrome (SJS/PTEN).
[PMID 8004131] The effect of CYP2C9 variants on drug metabolism should not be predicted without also considering CYP2C9*3, defined as the common loss of function variant rs1057910(C)  (NM_000771:c.430C>T, NP_000762:p.144R>C) .
[PMID 19422321] In a 2009 article titled "Genetically based impairment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine?" Authors reviewed prior research that argued:
- Individuals carrying minor alleles of this both CYP2C9*2 rs1799853 AND CYP2C8*3 (a minor allele of both rs10509681 and rs11572080) have 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.
- In addition, carriers of the risk allele for CYP2C9*2 rs1799853 have decreased metabolism of Ibuprofen, Flurbiprofen, Piroxicam, and Tenoxicam.
- The presence of CYP2C9*2 rs1799853 allele alone does not confer risk with Diclofenac, but when it is combined with CYP2C8*3 (rs10509681 and rs11572080), Diclofenac induces hepatoxicity and confers risk of GI bleeding.
[PMID 18216720] In a 2008 article (reviewed in [PMID 19422321]) titled "Interaction of CYP2C8 and CYP2C9 genotypes modifies the risk for nonsteroidal anti-inflammatory drugs-related acute gastrointestinal bleeding," the study discovered that carriers of CYP2C8*3 (a minor allele of both rs10509681 and rs11572080) had a GI bleeding event risk OR=1.81 (95% CI=0.95–3.46; P=0.071) and risk increased if carriers drank more than 20g alcohol/day to an OR=1.99 (95% CI=1.06–3.74; P=0.034). As CYP2C8*3 and CYP2C9*2 rs1799853 variant alleles are in linkage disequilibrium, patients are likely to carry the risk allele to both 8*3 and 9*2, and when they do, The OR (95% CI) for carriers of such a genotype is increased to 1.94 (1.13–3.33), P=0.017.
[PMID 18216720] A 2013 NIH review titled "PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 8" reiterated that "some data suggest that the combined presence of minor risk alleles CYP2C8*3 (rs10509681 and rs11572080) and CYP2C9*2 rs1799853 is a determinant of NSAID-induced gastrointestinal bleeding." They cited [PMID 18216720].
|Trait||Warfarin maintenance dose|
|Title||A Genome-Wide Association Study Confirms VKORC1, CYP2C9, and CYP4F2 as Principal Genetic Determinants of Warfarin Dose|
|Odds Ratio||0.54 [0.45-0.63] mg/week decrease|
[PMID 20214591] Pharmacogenomics in aspirin intolerance
[PMID 20555338] Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements
[PMID 22118051] Genetic variants in CYP (-1A2, -2C9, -2C19, -3A4 and -3A5), VKORC1 and ABCB1 genes in a black South African population: a window into diversity
[PMID 17048007] Association of warfarin dose with genes involved in its action and metabolism.
[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 18990750] Red meat intake, doneness, polymorphisms in genes that encode carcinogen-metabolizing enzymes, and colorectal cancer risk.
[PMID 18992148] Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study.
[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 19761371] Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies.
[PMID 19955245] Warfarin sensitivity genotyping: a review of the literature and summary of patient experience.
[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 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 23473641] Effect of CYP2C9 and VKORC1 genetic polymorphisms on mean daily maintenance dose of acenocoumarol in South Indian patients
[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 22676711] Pharmacogenomics of warfarin in populations of African descent.
[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 26265036] Genome-wide association study of warfarin maintenance dose in a Brazilian sample
[PMID 29425227] Interaction between polymorphisms in aspirin metabolic pathways, regular aspirin use and colorectal cancer risk: A case-control study in unselected white European populations.