A rapid-ACCE review of CYP2C9 and VKORC1 alleles testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding.

Department of Pathology and Laboratory Medicine, Women and Infants Hospital, Warren Alpert School of Medicine of Brown University, Providence, Rhode Island 02903, USA.
Genetics in medicine: official journal of the American College of Medical Genetics (Impact Factor: 6.44). 03/2008; 10(2):89-98. DOI: 10.1097/GIM.0b013e31815bf924
Source: PubMed

ABSTRACT Summarize evidence regarding genetic testing in adults to inform warfarin dosing to reduce adverse drug events such as serious bleeding.
Review published (and selected gray) literature using the Rapid-ACCE structure that addresses analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications.
Preliminary data suggest overall analytic sensitivity and specificity will be 98% or higher for CYP2C9 genotyping, but strength of evidence for analytic validity is low, especially for VKORC1 testing. Strength of evidence is high for the clinical validity of both genes in predicting stable warfarin dose, an intermediate outcome, but is low for the association between CYP2C9 testing and severe bleeding events (clinical sensitivity 46% (95% CI 32-60%); specificity 69% (95% CI 62-75%) and absent for bleeding events associated with VKORC1 testing. No data are available to document clinical utility of genotyping before warfarin dosing.
The most important gaps identified are: which variants should be included in a testing panel, lack of data from external proficiency testing, lack of validated dosing algorithm incorporating genetic and nongenetic factors, evidence of clinical utility, reliable economic analyses, and methods to address several ethical, legal, and social implications issues.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy. Using Vanderbilt's DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy. CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04). The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days.
    Pharmacogenomics 12/2014; 15(16):1973-83. DOI:10.2217/pgs.14.153 · 3.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background : Data on the prevalence of CYP2C9 and VKORC1 genes and their influence on anticoagulant effect and warfarin dose in stroke patients are scarce. The aim of this study was to determine the occurrence and significance of these gene polymorphisms and to establish pharmacogenetic algorithm to estimate the dose of introduction. Also, the goal was to determine tailored safety and intensity of anticoagulation response depending on the allelic variants and their impact on the clinical outcome in acute stroke patients in Croatia. Methods : A total of 106 consented acute stroke patients were tested for CYP2C9*2,*3 and VKORC1 1173C > T gene polymorphisms. We estimated the dose of introduction and monitored anticoagulant effect obtained by INR values, time to reach stable dose, stable maintenance dose, time spent within the therapeutic/supratherapeutic INR range, occurrence of dosage side effects and clinical outcome depending on genotypes. Results : We found that 83% of stroke patients in our study were carriers of multiple allelic variants. The predicted initial dose correlated with the stable warfarin maintenance dose (p = 0.0311) and we correctly estimated the dose for 81.5% of 61.3% of study patients who required higher/lower doses than average. Warfarin dosage complications were slightly more frequent among the carriers of CYP2C9*2,*3 compared to the carriers of VKORC1 1173 T alleles (68. 9% versus 62.5%), but their occurrence did not affect the final clinical outcome. Conclusion : Our data indicated rapid and safe anticoagulation achieved by using pharmacogenetically-predicted warfarin dose in high-risk acute stroke patients without increasing the risk of warfarin dosage complications in elderly population.
    Journal of the Neurological Sciences 08/2014; 343(1-2). DOI:10.1016/j.jns.2014.04.039 · 2.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction. Genetic testing services for disease prediction, drug responses, and traits are commercially available by several companies in Korea. However, there has been no evaluation study for the accuracy and usefulness of these services. We aimed to compare two genetic testing services popular in Korea with 23andMe service in the United States. Materials and Methods. We compared the results of two persons (one man and one woman) serviced by Hellogene Platinum (Theragen Bio Institute), DNAGPS Optimus (DNAlink), and 23andMe service. Results. Among 3 services, there were differences in the estimation of relative risks for the same disease. For lung cancer, the range of relative risk was from 0.9 to 2.09. These differences were thought to be due to the differences of applied single nucleotide polymorphisms (SNPs) in each service for the calculation of risk. Also, the algorithm and population database would have influence on the estimation of relative disease risks. The concordance rate of SNP calls between DNAGPS Optimus and 23andMe services was 100% (30/30). Conclusions. Our study showed differences in disease risk estimations among three services, although they gave good concordance rate for SNP calls. We realized that the genetic services need further evaluation and standardization, especially in disease risk estimation algorithm.
    BioMed Research International 06/2014; 2014:539151. DOI:10.1155/2014/539151 · 2.71 Impact Factor


Available from