|(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|
|qualified_impact||Moderate clinical importance, pharmacogenetic|
|summary||This variant, also called CYP2C9*2, is a pharmacogenetic variant that modulates sensitivity for Warfarin (due to reduced metabolism). This variant is associated with Caucasians. The FDA has approved reduced recommended Warfarin dosage based on the presence of this variant.|
|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|
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