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GWAS Implicates Cytochrome P450 Gene in Plavix Response

NEW YORK (GenomeWeb News) – A variant in a cytochrome P450 enzyme gene called CYP2C19 appears to influence Plavix response and treatment outcomes, according to a genome-wide association study appearing online today in the Journal of the American Medical Association.

A team of Baltimore researchers did a GWAS involving more than 400 Amish individuals, looking for genetic variants that influence response to the anti-clotting drug clopidogrel, marketed by Bristol-Myers Squibb and Sanofi-Aventis as Plavix. Their search identified more than a dozen SNPs in and around a cluster of cytochrome P450 genes that were linked to drug response.

One of the most statistically significant SNPs was in linkage disequilibrium with CYP2C19*2 — a variant implicated in Plavix response in the past. After doing follow-up studies involving individuals at risk of cardiovascular events, the researchers found ties between CYP2C19*2, Plavix effectiveness, and coronary events or death.

Treatment with Plavix and aspirin is meant to interfere with platelet binding to one another, reducing the risk of blood clots and cardiovascular events. But response to Plavix varies widely between individuals. Some of this variation has been attributed to environmental factors such as smoking, though much of it appears to be due to inherited factors.

As part of the Pharmacogenomics of Antiplatelet Intervention, or PAPI, study, lead author Alan Shuldiner, a researcher at the University of Maryland School of Medicine, and his colleagues did a GWAS involving 429 healthy Amish individuals.

The participants received clopidogrel for a week and the researchers gauged the drug's effectiveness by looking for ADP-stimulated platelet aggregation after they finished the therapy — something that should not occur if the drug works as intended. Study participants were genotyped using Affymetrix Gene Chip Human Mapping 500K or 1M arrays.

The researchers detected poorer drug response in older individuals as well as those with higher body mass index or elevated triglyceride levels. But these factors only explained about 10 percent of the variation in drug response observed.

They also detected associations between Plavix response and 13 SNPs on chromosome 10 that were in and around a cluster of four cytochrome P450 genes: CYP2C18, CYP2C19, CYP2C9, and CYP2C8.

And, the team noted, the nine individuals with the worst drug outcomes were homozygous for a SNP called rs12777823. On the other hand, 300 individuals who had the major allele of this variant had the best outcomes and those who were heterozygous for the allele showed intermediate drug response.

In addition, they found that this SNP was in linkage disequilibrium with CYP2C19*2 — a loss-of-function CYP2C19 variant previously implicated in reduced Plavix activity and more frequent cardiovascular events.

When the researchers compared the effects of Plavix alone or in conjunction with aspirin, they found that adding aspirin did not prevent platelet aggregation in those carrying the CYP2C19*2 variant.

The team verified the CYP2C19*2 effect in a follow-up study of 227 individuals from the Sinai Hospital of Baltimore Study. These individuals had undergone non-emergency percutaneous coronary intervention (such as angioplasty or other methods for widening coronary arteries) and were considered to be at increased risk of cardiovascular events.

These individuals had similar platelet aggregation profiles to one another before taking clopidogrel. But after the treatment, the researchers detected aggregation differences associated with the CYP2C19*2 variant. As in the Amish group, individuals with the allele had worse treatment response and more platelet aggregation.

In a subset of these individuals, the researchers found that CYP2C19*2 was linked to an increase in coronary events during a year of follow-up. The risk of cardiovascular events or death was nearly 21 percent in those carrying the CYP2C19*2 variant, compared with 10 percent in the other individuals tested.

Overall, the team concluded that the CYP2C19*2 variant accounts for an estimated 12 percent of the variation detected in Plavix response. That has the researchers calling for clinical trials that address whether testing for the CYP2C19*2 allele — which is found in nearly a quarter of Caucasian individuals, roughly 18 percent of Mexican-Americans, about a third of African-Americans, and just over half of Asian individuals — leads to more effective therapy.

"Those with the CYP2C19 genotype may benefit more from an antiplatelet regimen that does not include clopidogrel" the researchers wrote. "Prospective randomized clinical trials will be necessary to determine the efficacy of CYP2C19 genotype-directed therapy in evidence-based clinical decision making."

The team is also interested in exploring other potential sources of variation in clopidogrel response, including copy number changes and rare variants. "It's certainly possible that we're missing big signals that aren't covered by the chip," Shuldiner told GenomeWeb Daily News.

Although copy number variation is harder to assess than SNPs, since human CNVs aren't as well characterized, Shuldiner explained, the team is starting to look for CNVs that could influence Plavix response.

In addition, they plan to do exome sequencing studies in individuals at the upper and lower extremes of the clopidogrel response spectrum to look for rare variants related to drug response. These sequencing studies will rely on next-generation sequencing technology, Shuldiner said, though the team has not yet selected a specific platform.

Finally, Shuldiner noted that his team and researchers from other groups are in the process of forming a Pharmacogenomics of Clopidogrel Consortium to amass a larger number of clopidogrel-treated individuals for studies aimed at identifying additional rare and common variants related to drug response.

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