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Abstract
Introduction: Warfarin is a widely prescribed, efficacious oral anticoagulant. S-warfarin, the more active form, is metabolized by the cytochrome P450 (CYP)2C9 enzyme. The aim was to evaluate the influence of two CYP2C9 functional polymorphisms (*2 and *3) on warfarin dose in African–Americans, an unstudied population and Caucasians, and also to assess the effect of these polymorphisms on anticoagulation response after accounting for nongenetic factors and genetic factors that might also impact the dose–response relationship of warfarin. Patients and methods: A prospective cohort of 362 patients with a target international normalized ratio of between 2.0 and 3.0 were genotyped. Warfarin sensitivity stratified by genotype was investigated using univariate and multivariate analyses. Results: The maintenance dose of warfarin was significantly related to genotype (p < 0.01) (variant carriers: 31.25 mg/week; wild-type: 37.5 mg/week), even after adjustment for possible confounding factors (p = 0.046). However, the effect of genotype was restricted to Caucasians, in whom variant carriers had a significantly lower maintenance dose compared with wild-type homozygotes (unadjusted: p < 0.01; adjusted: p = 0.02). There was a greater risk of over-anticoagulation among Caucasian variant carriers, although this was only observed prior to reaching maintenance dose. For African–American variant carriers, there was no difference in warfarin response based on CYP2C9 genotype. Discussion: CYP2C9 *2 and *3 variants provide predictive information in anticoagulation response. However, these variants may not be useful in African–Americans or as a marker of long-term over-anticoagulation once a stable dose is reached.
Acknowledgements
Funded by National Institutes of Health grants R01HL066176–04 and P20RR020741. The authors thank Joseph A Gascho for serving as the site investigator at Hershey Medical Center. We are also indebted to Mitchell Laskin, Mabel Chin and Francis Herrmann for their dedication to our field work. Data have been submitted to PharmGKB at www.pharmgkb.org under the IN-RANGE project name.