Testing of VKORC 1 and CYP 2 C 9 alleles to guide warfarin dosing Test Category : Pharmacogenomic ( Treatment )

Warfarin is an oral anticoagulant that is widely prescribed to prevent thromboembolic events in persons at increased risk. The optimal dose is difficult to establish because it can vary 10-fold among individuals due to clinical and demographic factors. Testing for variants of the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes has been proposed for use in guiding the initial dose of warfarin, thus achieving optimal dosing more quickly and with lower risk of bleeding.

HuGE Navigator: query "warfarin and VKORC1" The ACCE review and ACMG guideline reported that there is evidence that CYP2C9 and VKORC1 variants are correlated with the stable warfarin dose.There is limited evidence for an association between CYP2C9 and severe bleeding events, and an absence of evidence for bleeding events associated with VKORC1.[3][4] Recent additions to the literature: A study designed to compare a clinical algorithm versus a pharmacogenetic algorithm using INR values (day 4 or 5 of treatment), clinical factors and genotype to predict warfarin dose.In the derivation set (N=969), the clinical algorithm had an coefficient of determination R(2) of 48% and the pharmacogenetic algorithm had an R(2) of 63% in predicting warfarin dose.In independent validation sets, the clinical algorithm had an R(2) of 26-43% and the pharmacogenetic algorithm had an R(2) of 42-58% in predicting warfarin dose.[7] A retrospective cohort study designed to examine the accuracy of pharmacogenetic warfarin dosing algorithms in predicting warfarin dose.Data from 71 adult patients at an outpatient anticoagulation clinic on a stable, therapeutic warfarin dose were included in the analysis.Six pharmacogenetic warfarin dosing algorithms and a 5 mg fixed dose approach were evaluated.The algorithms published by Gage et al. 2008 andthe IWPC 2009 were the most accurate in predicting warfarin dose in the study population.[8] A study designed to compare the International Warfarin Pharmacogenetics Consoritum (IWPC) algorithm versus a clinical algorithm in cohort of Japanese patients (n=200).The purpose was to determine the percentage of Japanese patients for whom the predicted dose deviated by less than 7mg/week from the actual dose.The IWPC algorithm identified a larger percentage of patients to achieve the target INR than did the clinical algorithm.[9] A study by the International Warfarin Pharmacogenetics Consortium reported a comprehensive assessment of the influence of six VKORC1 SNPs and haplotypes on warfarin dose prediction in a cohort of Asians (n=1103), blacks (n=670), and whites (n=3113).[10] VKORC1-1639G>A and 1173C>T individually explained the greatest variance in warfarin dose across the three racial groups.Including additional VKORC1 SNPS and haplotypes did not further improve warfarin dose prediction.
VKORC1 explained greater variability in warfarin dose among whites than in Asians or blacks, a finding explained largely by race-specific differences in the frequency of the -1639 A and 1173T alleles.
A study designed to examine the effect of CYP2C9 and VKORC1 genotypes on rate of International Normalized Ratio (INR) increase, anticoagulation maintenance, risk of over anticoagulation, and change in dose over 30 days.[11] The VKORC1 variant genotype (with/without the CYP2C9 variant genotype) was associated with higher risk of over anti-coagulation in European Americans but not African Americans.
The risk of minor hemorrhage was not influenced by either CYP2C9 or VKORC1 genotype.
* independent groups include the US Preventive Services Task Force (USPSTF) and Evaluation of GenomicApplications in Practice and Prevention (EGAPP) Working Group.

Evidence Overview
Analytic Validity : Test accuracy and reliability in identifying alleles at multiple SNPs (analytic sensitivity and specificity).
Based on findings from a ACCE evidence review and ACMG policy statement: Limited data on analytic validity are available from laboratories performing these tests.[4] High analytic sensitivity and specificity is expected for testing of common CYP2C9 alleles.[3] [4] Few data are available for evaluation on analytic sensitivity and specificity of testing for VKORC1alleles.The ACCE review and ACMG guideline reported that there is evidence that CYP2C9 and VKORC1 variants are correlated with the stable warfarin dose.There is limited evidence for an association between CYP2C9 and severe bleeding events, and an absence of evidence for bleeding events associated with VKORC1.[3][4] Recent additions to the literature: A study designed to compare a clinical algorithm versus a pharmacogenetic algorithm using INR values (day 4 or 5 of treatment), clinical factors and genotype to predict warfarin dose.In the derivation set (N=969), the clinical algorithm had an coefficient of determination R(2) of 48% and the pharmacogenetic algorithm had an R(2) of 63% in predicting warfarin dose.In independent validation sets, the clinical algorithm had an R(2) of 26-43% and the pharmacogenetic algorithm had an R(2) of 42-58% in predicting warfarin dose.[7] A retrospective cohort study designed to examine the accuracy of pharmacogenetic warfarin dosing algorithms in predicting warfarin dose.Data from 71 adult patients at an outpatient anticoagulation clinic on a stable, therapeutic warfarin dose were included in the analysis.Six pharmacogenetic warfarin dosing algorithms and a 5 mg fixed dose approach were evaluated.The algorithms published by Gage et al. 2008 andthe IWPC 2009 were the most accurate in predicting warfarin dose in the study population.[8] A study designed to compare the International Warfarin Pharmacogenetics Consoritum (IWPC) algorithm versus a clinical algorithm in cohort of Japanese patients (n=200).The purpose was to determine the percentage of Japanese patients for whom the predicted dose deviated by less than 7mg/week from the actual dose.The IWPC algorithm identified a larger percentage of patients to achieve the target INR than did the clinical algorithm.[9] A study by the International Warfarin Pharmacogenetics Consortium reported a comprehensive assessment of the influence of six VKORC1 SNPs and haplotypes on warfarin dose prediction in a cohort of Asians (n=1103), blacks (n=670), and whites (n=3113).[10] VKORC1-1639G>A and 1173C>T individually explained the greatest variance in warfarin dose across the three racial groups.Including additional VKORC1 SNPS and haplotypes did not further improve warfarin dose prediction.
VKORC1 explained greater variability in warfarin dose among whites than in Asians or blacks, a finding explained largely by race-specific differences in the frequency of the -1639 A and 1173T alleles.
A study designed to examine the effect of CYP2C9 and VKORC1 genotypes on rate of International Normalized Ratio (INR) increase, anticoagulation maintenance, risk of over anticoagulation, and change in dose over 30 days.[11] The VKORC1 variant genotype (with/without the CYP2C9 variant genotype) was associated with higher risk of over anti-coagulation in European Americans but not African Americans.
The risk of minor hemorrhage was not influenced by either CYP2C9 or VKORC1 genotype.
* independent groups include the US Preventive Services Task Force (USPSTF) and Evaluation of GenomicApplications in Practice and Prevention (EGAPP) Working Group.
[3]    College of American Pathology (CAP)/American College of Medical Genetics proficiency testing program for warfarin pharmacogenetic testing may improve access to analytic validity data.[3][4]http://www.cap.org/apps/docs/proficiency_testing/surveys_catalog/2010_surveys_catalog.pdf#page=214ClinicalValidity : Test accuracy and reliability in predicting appropriate warfarin dose (predictive value).Published studies have examined the relationship of CYP2C9 alleles to warfarin dose.[6]HuGE Navigator: query "warfarin and CYP2C9" Published studies have examined the relationship of VKORC1 alleles to warfarin dose.[6]HuGE Navigator: query "warfarin and VKORC1"