Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes

Abstract

Background: The influence of CYP2C9 and VKORC1 polymorphisms on warfarin dose has been investigated in white, Asian, and African American populations but not in Puerto Rican Hispanic patients.

Objective: To test the associations between genotypes, international normalized ratio (INR) measurements, and warfarin dosing and gauge the impact of these polymorphisms on warfarin dose, using a published algorithm.

Methods: A retrospective warfarin pharmacogenetic association study in 106 Puerto Rican patients was performed. DNA samples from patients were assayed for 12 variants in both CYP2C9 and VKORC1 loci by HILOmet PhyzioType assay. Demographic and clinical nongenetic data were retrospectively collected from medical records. Allele and genotype frequencies were determined and Hardy-Weinberg equilibrium (HWE) was tested.

Results: Sixty-nine percent of patients were carriers of at least one polymorphism in either the CYP2C9 or the VKORC1 gene. Double, triple, and quadruple carriers accounted for 22%, 5%, and 1%, respectively. No significant departure from HWE was found. Among patients with a given CYP2C9 genotype, warfarin dose requirements declined from GG to AA haplotypes; whereas, within each VKORC1 haplotype, the dose decreased as the number of CYP2C9 variants increased. The presence of these loss-of-function alleles was associated with more out-of-range INR measurements (OR = 1.38) but not with significant INR >4 during the initiation phase. Analyses based on a published pharmacogenetic algorithm predicted dose reductions of up to 4.9 mg/day in carriers and provided better dose prediction in an extreme subgroup of highly sensitive patients, but also suggested the need to improve predictability by developing a customized model for use in Puerto Rican patients.

Conclusions: This study laid important groundwork for supporting a prospective pharmacogenetic trial in Puerto Ricans to detect the benefits of incorporating relevant genomic information into a customized DNA-guided warfarin dosing algorithm.

Conflict of interest statement

Conflict of interest: Dr. Ruaño is founder and president of Genomas Inc.; Mr. Kocherla, Ms. Gorowski, and Ms. Bogaard are full-time employees of Genomas, and Dr. Seip is a consultant to Genomas Inc. This investigation received support from the NCRR Research Centers in Minority Institutions Award Grant G12RR-03051; Grant SC2HL110393-01 from the National Heart, Lung and Blood Institute/National Institutes of Health, and Genomas internal research and development funds.

Figures

Figure 1

Box and whisker plots representing association of CYP2C9 and VKORC1-1639 G>A polymorphisms (abscissa) with actual warfarin dose (ordinate) in 97 Puerto Rican patients at San Juan Veterans Affairs Caribbean Healthcare System. CYP2C9 genotype is labeled as wild-type (*1/*1), 1 variant allele (*1/*2, *1/*3, or *1/*5), or 2 variant alleles (*2/*2, *2/*3, *2/*5). Within each CYP2C9 genotype, the VKORC1 genotype at −1639 G>A is shown as GG, GA, or AA. Individual values for each group are depicted as open circles. Median warfarin daily doses in each of the 9 subgroups by genotypes are represented by horizontal bars. Two-tailed p values correspond to nonparametric Mann-Whitney U (rank-sum) test results after comparing 2 different pairs of observed genotype groups.

Figure 2

Predicted mean decreases in warfarin dose in the average patient (N = 97; aged 66.5 years, 171 cm, 85.9 kg), based on observed genotypes and clinical/demographic data. The filled areas indicate ranges of predicted dose reductions based on the published genetic algorithm.