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Large UK GWAS Underscores Impact of CYP2C9, VKORC1, New SNP in Warfarin-Dosing Variability

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A recently published genome-wide association study provides further scientific evidence that patients with variations in two well-known genes, VKORC1 and CYP2C9, and a third lesser-known gene, CYP4F2, are more likely to have adverse reactions to the anticoagulant warfarin.

In the study, researchers from the Wellcome Trust Sanger Institute and elsewhere looked at approximately 326,000 SNPs in 1,053 Swedish subjects. They believe their work is the first "sufficiently powered" trial to detect genome-wide significance of the three SNPs. As a result, "additional genes having a major influence on warfarin dose might not exist or be found in the near-term," the study authors claim.

Published in PLoS Genetics last week, the study corroborated previously published research that around 30 percent and 12 percent of the variability in patients' response to warfarin are contributed by abnormalities in the CYP2C9 and VKORC1 genes, respectively.

The researchers also found that CYP4F2, a relatively newly discovered gene, accounted for around 1.5 percent of the variability tied to warfarin dose response. The research team confirmed this association in another 600-patient cohort.

The researchers used the Illumina HumanCNV370 BeadChip and two additional VKORC1 and CYP2C9 SNPs from the Applied Biosystems' TaqMan assay. The subjects were enrolled through the Warfarin Genetics study, a multi-center study of warfarin-related bleeding complications and treatment response.

The researchers also looked at copy-number variations, haplotypes, and imputed SNPs, but "found no additional highly significant warfarin associations."

Excluding CYP2C9, VKORC1, and CYP4F2, lead author Panos Deloukas and colleagues identified 40 other GWAS loci exhibiting multivariate regression p-values below 0.0002 for follow-up genotyping, and selected 40 SNPs representing these loci for genotyping using Sequenom's iPLEX MassARRAY.

The 40 "SNPs we tested did not yield any promising candidates in our replication effort, [but] we are in the process of conducting a meta analysis of genome-wide association data that will further increase sample size and may allow us to detect weaker effects," Deloukas, a senior investigator in human genetics at the Sanger Institute, told Pharmacogenomics Reporter this week.

The researchers noted that their analysis, with 80 percent power to detect genome-wide significance of common dose-response variants, was generalizeable to other studies.

"These GWAS results provide further impetus for conducting large-scale trials assessing patient benefit from genotype-based forecasting of warfarin dose," the study authors said.

Two years ago, the US Food and Drug Administration asked manufacturers of warfarin to update the drug's label with information explaining how genotypes may impact how patients' respond to the drug [see PGx Reporter 09-05-2007].

The drug's label today notes that the variant alleles CYP2C9*2 and CYP2C9*3 decrease a patient's ability to clear warfarin. Other CYP2C9 alleles mentioned in the warfarin label linked to reduced enzymatic activity at lower frequencies, include *5, *6, and *11 alleles in those of African ancestry and *5, *9, and *11 alleles in Caucasians. With regard to VKORC1, the label highlights that the -1639G>A allele has been associated with the need to lower doses of warfarin in patients.

The label currently does not mention the newly identified CYP4F2 gene, nor does it mention pharmacogenomics-guided dosing information for the drug.

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CYP4F2 in Next Label Update?

The FDA has previously stated its intent to re-update wafarin's label with pharmacogenomics-guided dosing information [see PGx Reporter 10-22-2008], and has said it is working with the Harvard-Partners Center for Genetics and Genomics to develop a gene-based warfarin dosing algorithm [see PGx Reporter 12-05-2007].

Since the labeling update in 2007, "more prospective and retrospective studies have been reported in the literature [about PGx-guided warfarin dosing]. We are actively looking into these data to determine if it would be possible and feasible to link label recommendations on dosing with genotypes of 2C9 and VKORC1," Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceutics in the FDA's Center for Drug Evaluation and Research, previously told Pharmacogenomics Reporter.

When asked whether the agency is considering including information about the CYP4F2 variant in its next update of the warfarin label, an FDA spokesperson said this week the agency couldn't comment on an ongoing regulatory issues.

Because CYP4F2 explains only around 1.5 percent of the warfarin dose-response variance, "the gain in improving the predictive ability of a model using this information is rather modest," Deloukas said.

"However, a test with three versus two SNPs should come at no extra cost and therefore should be useful to include," Deloukas added.

Genetic tests for warfarin sensitivity cost between $300 and $500. Autogenomics, one company that tests for rare CYP2C9 and VKORC1 variants, charges around $100 for every variant tested [see PGx Reporter 10-10-2007]. It is unclear if any diagnostic testing companies have begun testing for variants in CYP4F2.

Several other researchers have looked at the validity of CYP4F2 in adjusting warfarin doses.

A year ago, researchers from Marshfield Clinic published a study in Blood identifying that CYP4F2 had a clinically relevant effect on warfarin dosing.

In February, Borgiani et al. published a study in Pharmacogenomics which found that 7 percent of mean weekly warfarin dose variance is explained by CYP4F2 and combining CYP4F2, CYP2C9 and VKORC1 genetic variants, age and weight, explains 60.5 percent of the inter-individual variability. "Our data confirm and strengthen the role of [CYP4F2]," the authors concluded.

Future Studies

In the future, the researchers plan to look at larger sample sizes and may directly compare the genetics of warfarin-treated individuals who experience bleeding events with those who don't, Deloukas told PGx Reporter sister publication GenomeWeb Daily News. He also highlighted the need to expand this type of research to other ethnic groups from Asia and Africa

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According to Deloukas, as several large gene-based warfarin trials near completion, more researchers will be searching for rare variants linked to warfarin response. Their search will be aided by advances in sequencing technology.

"New sequencing technologies will allow us to tackle [rare variants] in a more efficient way because we can really search the entire genome," Deloukas said.

One of the limitations to the PLoS Genetics study was that the iPLEX Massarray did not allow sufficient power to detect copy number variations or lower frequency variants.

"For future studies we will be using the best available array at the time," Deloukas told Pharmacogenomics Reporter. "We also envisage going into resequencing, especially for the bleeding phenotype, which is rare."

He noted that this research was part of a larger UK-based warfarin study that will eventually look into cost-effectiveness. "We are not directly involved in clinical-utility studies, although a European consortium with many of our clinical collaborators was funded to initiate such work," he said.

Other groups have started assessing the usefulness and cost effectiveness of using genetic variants to guide warfarin dosing. For example, a study published in the New England Journal of Medicine last month suggests that genetic testing for CYP2C9 and VKORC1 polymorphisms improves warfarin dose predictions for those who need relatively high or low doses of the drug.

And a study published in the Annals of Internal Medicine in January indicates that warfarin genetic testing is only cost effective for dosing individuals at high risk of hemorrhaging [see PGx Reporter 01-21-2009].

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