The aim of the study is to explore the contribution of genetic factors related either to drug metabolism (cytochrome P450 2C9) or to drug target (vitamin K epoxide reductase) to variability in the response to acenocoumarol among 222 healthy volunteers after a single oral dose. Associations between a pharmacodynamic index (reduction in factor VII activity and international normalized ratio [INR] change) and several genetic polymorphisms (VKORC1: ؊4931T>C, ؊4451C>A, ؊2659G>C, ؊1877A>G, ؊1639G>A, 497C>G, 1173C>T, and CYP2C9*3) were investigated using haplotype and univariate analyses. VKORC1 haplotypes were associated with the pharmacologic response, and this association can be explained only by the effect of the ؊1639G>A polymorphism (or alternatively by 1173C>T, which is in complete association with it). Indeed, it explains about one third of the variability of the pharmacologic response (37% of factor VII decrease and 30% of INR change). Moreover, the previously observed effect of the CYP2C9*3 allele is independent of the VKORC1 gene effect. These 2 polymorphisms account for up to 50% of the interindividual variability. The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 ؊1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy. (Blood. 2005;106:135-140)

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Age and prior use of psychotropic agents are associated with postoperative morphine dose requirements. Whether ABCB1 polymorphisms might predict morphine side effects remains to be determined.