rs1799853

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). 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 rs1799853(T) allele encodes a variant amino acid, cysteine, which has been linked to poor metabolism of warfarin and thus sensitivity. 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). 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) ncbi.nlm.nih.gov (NM_000771:c.430C>T, NP_000762:p.144R>C) pharmgkb.org. 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. In a 2008 article (reviewed in ) 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. 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 . Association of warfarin dose with genes involved in its action and metabolism. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans. Genotyping panel for assessing response to cancer chemotherapy. The largest prospective warfarin-treated cohort supports genetic forecasting. Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients. Genetic factors contribute to patient-specific warfarin dose for Han Chinese. Warfarin pharmacogenetics. Red meat intake, doneness, polymorphisms in genes that encode carcinogen-metabolizing enzymes, and colorectal cancer risk. Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study. Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. Polymorphic variation in NFKB1 and other aspirin-related genes and risk of Hodgkin lymphoma. Thrombotic genetic risk factors and warfarin pharmacogenetic variants in Sao Miguel's healthy population (Azores). Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies. Warfarin sensitivity genotyping: a review of the literature and summary of patient experience. Genetic variants involved in gallstone formation and capsaicin metabolism, and the risk of gallbladder cancer in Chilean women. Pharmacogenetics of acenocoumarol in patients with extreme dose requirements. Cyclophosphamide-metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study. A novel, single algorithm approach to predict acenocoumarol dose based on CYP2C9 and VKORC1 allele variants. Warfarin genotyping using three different platforms. Are cytochrome P450 CYP2C8 and CYP2C9 polymorphisms associated with ibuprofen response in very preterm infants? VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children. Influence of genetics and non-genetic factors on acenocoumarol maintenance dose requirement in Moroccan patients. PharmGKB summary: phenytoin pathway.