121A genome-wide association study found gene polymorphisms that affect the
anticoagulant effect of warfarin (Takeuchi et al. 2009 ). The study confi rmed
VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin
dose. They also thoroughly investigated copy number variations, haplotypes, and
imputed SNPs, but found no additional highly signifi cant warfarin associations.
These results provide justifi cation for conducting large-scale trials assessing patient
benefi t from genotype-based forecasting of warfarin dose. A multicenter, random-
ized, controlled trial of warfarin involving patients with atrial fi brillation or venous
thromboembolism in whom genotyping for CYP2C92, CYP2C93, and VKORC1
(−1639G → A) was performed with the use of a POC test (Pirmohamed et al. 2013 ).
Results showed that pharmacogenetic-based dosing was associated with a higher
percentage of time in the therapeutic INR range than was standard dosing during the
initiation of warfarin therapy. An individualized dose forecasting based on a patient’s
genetic makeup at VKORC1, CYP2C9 and possibly CYP4F2 could provide state-
of-the-art clinical benchmarks for warfarin use during the foreseeable future.
Role of Pharmacogenetics in Antiplatelet Therapy
The antiplatelet agent clopidogrel (Plavix) is used in the management of cardiovas-
cular disease and stroke, but genetic mutations may reduce the effect of this drug.
The reduced-function CYP2C19 allele is present in around 30 % of people of
European ancestry and more than 40 % of those of African or Asian ancestry.
Persons with these gene variants carry double or triple the risk of death, myocardial
infarction or stroke, compared with people with the normal metabolism alleles.
It has been suggested that clopidogrel may be less effective in reducing the rate
of cardiovascular events among persons who are carriers of loss-of-function
CYP2C19 alleles that are associated with reduced conversion of clopidogrel to its
active metabolite. Lack of anticipated platelet response may be due to development
of resistance to clopidogrel, which is likely due to a polymorphism of the CYP2C19
gene (Ford 2009 ). One study found that determination of ABCB1 genotype in addi-
tion to CYP2C19 enables better prediction of clopidogrel nonresponsiveness
(Momary et al. 2010 ). The FDA has changed clopidogrel’s prescribing information
to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics,
pharmacodynamics and clinical response (Ellis et al. 2009 ). However, another study
in patients with acute coronary syndromes or atrial fi brillation has shown that the
effect of clopidogrel as compared with placebo is consistent, irrespective of
CYP2C19 loss-of-function carrier status (Paré et al. 2010 ).
In 2009, Scripps Health was the fi rst health system in the US to deploy Quest/
Scripps CYP2C19 genetic testing service for coronary stent patients receiving
Plavix. As of March 2011, Quest is collaborating with Scripps Translational Science
Institute to develop the Plavix-Response test for 3 M Integrated Cycler to personal-
ize treatment with Plavix based on a patient’s CYP2C19 genotype in less than 1 h.
Spartan Bioscience launched a DNA testing system in 2010 for the CYP2C19*2
mutation that guides how patients metabolize Plavix. It is currently in a clinical trial
Role of Pharmacogenetics in Pharmaceutical Industry