Genetic variability is linked to differences in response to warfarin therapy

March 6, 2008 By Vijayalakshmi Kunadian MBBS MD MRCP [mailto:vkunadian@perfuse.org]

Nashville: Researchers have demonstrated that genetic variability in the enzymes that metabolize warfarin is associated with variations in INR response

Previous studies have demonstrated an association between the genes encoding the cytochrome P-450 2C9 enzyme and vitamin K epoxide reductase (VKORC1) and variability in sensitivity to warfarin therapy. Individual contributions of these genetic components are not known. Therefore, Schwarz and co-workers in a study published in the recent issue of the New England Journal of Medicine determined the genetic variants of the enzyme cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) and their impact on response to warfarin therapy. Briefly, CYP2C9 is responsible for the metabolic clearance of warfarin whereas VKORC1 which converts vitamin K reductase to the reduced form of vitamin K, is the target of coumarin anticoagulants.

Genotyping was carried out among 297 patients aged >18 years who were treated with warfarin therapy for various clinical conditions (atrial fibrillation 36%, joint replacement 40.7%, thrombosis or embolus 13.5% other or multiple indications 11.1%) from July 2002 to July 2004 at the Vanderbilt University Medical Center, Nashville. Patients with cancer and excess alcohol consumption were excluded from the study. The investigators determined the clinical characteristics, response to therapy measured by INR levels and bleeding events.

The main study outcome measures consisted of
 * 1) Time to first therapeutic INR
 * 2) Time to first INR greater than 4
 * 3) Time above the therapeutic INR range
 * 4) INR response over time
 * 5) Warfarin dose requirement

Using genotyping for VKORC1, patients were grouped into those with haplotype group A and group non-A. The major variant alleles for CYP2C9 were CYP2C9*2 and CYP2C9*3.

The target INR range among study patients was 1.8-3.5 and it was 2-3 in 69% of the cases. The average initial warfarin dose was 4.8±0.8 mg. Patients were followed up for a median of 43 days. The allelic frequency of haplotype A was 32.6% and the allelic frequency of CYP2C9*2 and CYP2C9*3 was 12% and 4.8% respectively.

In terms of impact on the clinical outcome, VKORC1 had significant effect on time required to reach first INR within therapeutic range (p=0.02) and the time to first INR of greater than 4 (p=0.003). The rate of achieving first therapeutic INR and the rate of reaching INR>4 was higher in the A/A homozygotes compared with non-A/non-A homozygotes (p<0.001, 0.009 respectively). Patients with haplotype A spent more time above the therapeutic range compared to the non-A haplotype patients (18.8% vs. 9.1%, p=0.02). The INR response was affected by VKORC1 haplotype during the first 2 weeks of treatment with warfarin.

On the other hand, CYP2C9 genotype did not significantly affect the time to first INR within therapeutic range but CYP2C9*2 and CYP2C9*3 variant alleles did reach INR >4 earlier than the wild type allele (p=0.03). A low dose of warfarin was required with haplotype A VKORC1 but the warfarin dose requirement was not markedly influenced by CYP2C9 variant alleles during the first 2 weeks of therapy although there was an association with warfarin dose after the first 28 days.

This study demonstrates that genetic variability in VKORC1 (particularly haplotype A variants), rather than CYP2C9 variability is strongly associated with initial variability in the response to warfarin therapy. This has important implications in clinical practice particularly among patients who reach target INR rapidly and have increased bleeding tendency. Although genetic testing is not readily available for all patients, the results from this study provide important insight into the genetic variability among patients who have varied response to warfarin therapy.