EXOME: New Genetic Sequencing Zeroes in on Clopidogrel Response Variants

CHICAGO, IL—An exploratory genetic sequencing method has identified new and previously known variants downstream of clopidogrel metabolism that appear to influence on-treatment reactivity after percutaneous coronary intervention (PCI), according to results of the EXOME study presented March 24, 2012, at the annual American College of Cardiology/i2 Scientific Session. Over longer-term follow-up, the CYP2C18/19 locus is the primary protein-coding determinant of clopidogrel response variability.

Researchers led by Matthew J. Price, MD, of the Scripps Translational Research Institute (La Jolla, CA), acquired 1,152 samples obtained at platelet function screening or during follow-up from patients participating in the GRAVITAS trial at 42 sites. On-treatment reactivity was assessed using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) at baseline and 30 days. Caucasian patients (n = 192) were selected for whole exome analysis, which involves sequencing all protein coding regions of the human genome, and unlike genome-wide association studies, can identify actual, causative variants associated with disease.

After quality control measures were taken, the sample number fell to 147 with 262,292 single nucleotide polymorphisms (SNPs) and 36,831 insertion/deletions. In addition to CYP2C18/19, 2 loci were linked to on-treatment reactivity (table 1).

Table 1. Loci Associated with On-Treatment Reactivity

However, at 30 days, only the CYP2C18/19 locus remained associated with clopidogrel response.

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“These findings are preliminary, but the identification of two genes critical to platelet function among the 21,000 sequenced without any hypothesis lends credibility to the validity of the results,” Dr. Price said, adding that it is unlikely that any other protein-coding variant currently has a large effect on clopidogrel response variability.

This study demonstrates “the feasibility and potential of exploratory pharmacogenomics using exome sequencing to identify unanticipated mechanisms of drug response,” he continued.

Going forward, Dr. Price said he would like to increase the exome sequencing sampling size and validate the variants in a larger patient cohort, in addition to completing functional modeling based on the SNPs found.

Panel co-chair George D. Dangas, MD, PhD, of Mount Sinai Medical Center (New York, NY) said he was “surprised that we didn’t see much contribution from genes related to clopidogrel absorption,” but Dr. Price attributed this potentially to the cohort analyzed.

“The enzyme that’s been implicated the most is ABCP1. The data for ABCP1 is inconsistent and some studies show that when you think that there’s an increase in a factor there’s actually a decrease,” he said, noting that ABCP1 had no effect in the GIFT cohort, a soon to be published, hypothesis-driven subanalysis of EXOME.

Source:

Price MJ. First pharmacogenomics analysis using whole exome sequencing to identify novel genetic determinants of clopidogrel response variability: Results of the Genotype Information and Functional Testing (GIFT) EXOME study. Presented at: American College of Cardiology Scientific Session; March 24, 2012; Chicago, IL.

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