ClinVar Genomic variation as it relates to human health

The arg144-to-cys (R144C) substitution results from a 430C-T transition in the CYP2C9 gene and is also known as rs1799853 and CYP2C9*2. The variant leads to reduced warfarin metabolism and increased risk of bleeding (Ross et al., 2010). Extensive interindividual variation in the response to a given dose of warfarin (coumarin) makes the prediction of an accurate maintenance dose difficult, with an effective daily dose ranging from 0.5 to 60 mg. The asymmetric carbon of warfarin (C9) gives rise to 2 enantiomeric forms, R-warfarin and S-warfarin, which are differentially metabolized. When administered as a racemate, S-warfarin is about 3 times as potent as R-warfarin. CYP2C9 is the principal enzyme that catalyzes the conversion of S-warfarin to inactive 6-hydroxy and 7-hydroxy metabolites, whereas the oxidative metabolism of R-warfarin is mainly catalyzed by CYP1A2 (124060) and CYP3A4 (124010). In addition to the wildtype CYP2C9*1 allele, point mutations in the CYP2C9 gene result in 2 allelic variants: CYP2C9*2, where cysteine substitutes for arginine at amino acid 144, and CYP2C9*3, where leucine substitutes for isoleucine at residue 359 (601130.0001). Both allelic variants have impaired hydroxylation of S-warfarin when expressed in vitro; the CYP2C9*3 variant is less than 5% as efficient as the wildtype enzyme, while CYP2C9*2 shows about 12% of wildtype activity, apparently as a result of the amino acid substitution altering the interaction of the enzyme with cytochrome P450 oxidoreductase. Aithal et al. (1999) studied the frequency of the 2 variant alleles in individuals with a low warfarin dose requirement; see 122700. Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy and had an increased risk of major bleeding complications. King et al. (2004) concluded that the coding region nonsynonymous polymorphisms associated with the CYP2C9*2 and CYP2C9*3 (601130.0001) alleles are the major CYP2C9-related factors affecting warfarin dose in U.K. Caucasians. Upstream CYP2C9 polymorphisms did not appear to be important independent determinants of dose requirement. In a metaanalysis of studies of the CYP2C9*2 and CYP2C9*3 (601130.0001) alleles, Sanderson et al. (2005) found that patients carrying these alleles had lower mean daily warfarin dosage and greater risk of bleeding. However, Li et al. (2006) could only partially confirm this. They found that polymorphisms in the VKORC1 gene (608547) were strongly associated with warfarin dosage requirement. They found no association with either of the 2 CYP2C9 polymorphisms studied, CYP2C9*2 and CYP2C9*3. CYP2C9*3 was significantly (p = 0.05) associated with average warfarin dosage after adjustment for the VKORC1*1173 polymorphism. Ross et al. (2010) genotyped 963 individuals from 7 geographic regions for the CYP2C9*2 and CYP2C9*3 variants. The CYP2C9*2 allele was primarily restricted to European (2 to 29%), Middle Eastern (11 to 20%) and Central/South Asia populations (2 to 16%), and was mostly absent in other population groups, such as Africa and the Middle East. Exceptions included the North Eastern Bantu from Africa (4%), the Yakut from East Asia (2%) and the Maya (2%). Similar frequencies were found in a Canadian cohort of 316 individuals of European, East Asian, and South Asian ancestry. (less)