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Researchers Start Untangling Warfarin Pharmacogenomics

NEW YORK (GenomeWeb News) – New research is dissecting the relative importance of polymorphisms in two genes linked to warfarin dose response.

In a study published online in the New England Journal of Medicine today, researchers from Vanderbilt University discussed how different variants contribute to warfarin response, influencing how long it takes patients to benefit from the treatment and to exceed the therapeutic dose.

One of the two genes, in particular, seems to predict the time it takes to achieve a therapeutic warfarin dose.

Warfarin is an anticoagulant used to treat thromboembolisms, blood clots that can clog blood vessels and cause conditions such as pulmonary embolisms and strokes. Warfarin works by acting on an enzyme called vitamin K epoxide reductase, which modifies an essential blood clotting cofactor. But warfarin’s therapeutic range is narrow and taking too much can lead to excessive anti-coagulation and hemorrhaging.

This is complicated by the fact that the amount of warfarin needed to reach this therapeutic window is widely variable depending on the individual. For instance, there is evidence that polymorphisms in VKORC1, the gene coding for vitamin K epoxide reductase, and CYP2C9, a gene coding for cytochrome P-450 2C9, an enzyme that helps clear warfarin metabolites, affect an individual’s warfarin response.

Consequently, the US Food and Drug Administration approved a label change for warfarin last August, highlighting the importance of considering lower initial warfarin doses depending on a patient’s VKORC1 and CYP2C9 variants.

In an effort to tweak apart the relative influence of VKORC1 and CYP2C9 variants, lead author Ute Schwarz, a Vanderbilt pharmacologist, and colleagues followed 297 patients taking warfarin from the time their treatment started to the end of their treatment or related follow-up. The target therapeutic INR range varied by patient since it was physician-determined.

The team genotyped CYP2C9 using an oligonucleotide ligation assay and fluorescent alleles, classifying the variants as CYP2C9*1, CYP2C9*2, and CYP2C9*3. They also genotyped the promoter of a second gene, VKORC1, using a custom TaqMan SNP array, classifying the variants into two haplotype groups, A and non-A.

By combining the CYP2C9 and VKORC1 data with data on how long it took each patient to reach the therapeutic range while taking warfarin and how long they stayed there, the team was able to address how these genetic variants influenced warfarin treatment outcomes.

As it turned out, polymorphisms in VKORC1 had a greater influence on the time it took patients to see a therapeutic effect than polymorphisms in the cytochrome P-450 2C9 gene CYP2C9. In fact, individuals who carried two A VKORC1 alleles reached this therapeutic window at about twice the rate of those carrying two non-A alleles. They also shot above the therapeutic range, associated with excess bleeding, more quickly.

In contrast, CYP2C9 polymorphisms, which influence warfarin metabolism, were not predictors of the time it took to get a therapeutic effect. They did predict the time it took to exceed the therapeutic range, though.

An editorial by National Institutes of Health researchers Susan Shurin and Elizabeth Nabel, also published in NEJM today, said the study “confirms the importance of genetic variation in influencing drug metabolism and response to therapy.” Still, the authors shied away from endorsing widespread pharmacogenomics in general, urging more research and clinical trials to evaluate the effectiveness of gene-based prescribing.

“These findings add important information to the body of knowledge about the pharmacogenetics of warfarin,” Shurin and Nabel wrote, “but they also remind us that the warfarin story is far from complete.”

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