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GWAS Links CYP2C19 to Plavix Response; Randomized-Controlled Trial, PGx Consortium to Come

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By Turna Ray

University of Maryland researchers have confirmed in a genome-wide association study that the CYP2C19*2 polymorphism plays a "major role" in how patients respond to the anti-clotting drug Plavix (clopidogrel).

The researchers now plan to conduct a prospective, randomized-controlled trial and form a pharmacogenomics consortium specifically focused on validating and discovering new gene-response variants for the drug.

The scientists published their findings from the GWAS, the first to study how CYP2C19*2 affects Plavix response and treatment outcomes, in the Journal of the American Medical Association this week.

The study, involving more than 400 Amish individuals, identified 13 SNPs near or in a cluster of cytochrome P450 genes linked to Plavix response. Of these, CYP2C19*2 showed to be the most statistically significant and was found to be associated with Plavix effectiveness, as well as the risk of coronary events or death.

A few months ago, the US Food and Drug Administration updated the label for Plavix with pharmacogenetic data informing doctors and patients of diminished response to the drug and increased risk of heart attack in patients with reduced CYP2C19 function [see PGx Reporter 06-17-2009].

According to Alan Shuldiner, lead study author and director of the genetic and genomic medicine program at the University of Maryland's School of Medicine, researchers are planning a prospective RCT comparing genotype-directed anti-platelet therapy to standard-of-care anti-platelet therapy.

"Results from such an RCT will be necessary to determine whether this discovery should be translated into clinical practice on a wider scale," Shuldiner told Pharmacogenomics Reporter this week.

Following FDA's update to the Plavix label, at least one national insurer, Aetna, said that the FDA did not provide enough information in the updated Plavix label to warrant coverage for the intervention. Plavix is marketed by Bristol-Myers Squibb and Sanofi Aventis.

Although CYP2C19 testing is already available commercially, "it is not utilized very much presently in clinical practice," Shuldiner noted.

As a result of this study, researchers concluded that the CYP2C19*2 variant accounts for an estimated 12 percent of the variation detected in Plavix response.

The CYP2C19*2 variant is found in nearly 25 percent of Caucasians, roughly 18 percent of Mexican-Americans, around 33 percent of African-Americans, and more than 50 percent of Asian individuals.

To drive adoption of CYP2C19 testing, not only will Shuldiner's group conduct a prospective RCT, but they also plan to work in collaboration with other groups to discover new variants linked to Plavix response.

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According to Shuldiner, the so called Clopidogrel Pharmacogenomics Consortium will be open to all investigators and clopidogrel research groups who wish to participate. "They will need to have blood or DNA for the genetic analyses" to join the consortium, Shuldiner said.

Study Details

In the GWAS published in JAMA, Shuldiner and his team analyzed samples from more than 400 Amish individuals enrolled in the Pharmacogenomics of Antiplatelet Intervention trial, or PAPI. In the study, researchers gauged the effectiveness of Plavix by monitoring ADP-stimulated platelet aggregation following a week-long treatment regimen. If the drug works as intended, ADP-stimulated platelet aggregation should not occur. Study participants were genotyped using Affymetrix Gene Chip Human Mapping 500K or 1M arrays.

Researchers attributed the majority of the drug response variation to 13 SNPs on chromosome 10 that were in and around a cluster of four cytochrome P450 genes: CYP2C18, CYP2C19, CYP2C9, and CYP2C8.

Furthermore, "the relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention," the study authors wrote in the JAMA paper. "Patients with the CYP2C19*2 variant were more likely to have a cardiovascular ischemic event or death during one-year follow-up."

Nine individuals with the worst drug outcomes were homozygous for a SNP called rs12777823, but 300 individuals who had the allele also experienced the best outcomes and those who were heterozygous for the allele showed intermediate drug response.

Additionally, the rs12777823 allele was in "strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12 percent of the variation in platelet aggregation to ADP," the study authors said in the paper. Even when Plavix was administered with aspirin, which helps mitigate platelet aggregation, this approach did not prevent platelet aggregation in those carrying the CYP2C19*2 variant.

The variation in drug response in approximately 10 percent of study participants could be attributed to higher age, body mass index, or triglyceride levels.

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

Analysis of this group revealed that as in the Amish group, individuals with the rs12777823 allele had worse treatment response and more platelet aggregation. Furthermore, in a subset of these individuals, 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.

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

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