Mutational analysis clopidogrel resistance and platelet function in patients scheduled for coronary artery bypass grafting

Mick Correll; Christopher K Johnson; Giovanni Ferrari; Mariano Brizzio; Andrew W C Mak; John Quackenbush; Richard E Shaw; Alex Zapolanski; Juan B Grau

doi:10.1016/j.ygeno.2013.01.005

Mutational analysis clopidogrel resistance and platelet function in patients scheduled for coronary artery bypass grafting

Genomics. 2013 Jun;101(6):313-7. doi: 10.1016/j.ygeno.2013.01.005. Epub 2013 Feb 24.

Authors

Mick Correll¹, Christopher K Johnson, Giovanni Ferrari, Mariano Brizzio, Andrew W C Mak, John Quackenbush, Richard E Shaw, Alex Zapolanski, Juan B Grau

Affiliation

¹ Department of Biostatistics and Computational Biology and Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Abstract

Clopidogrel is an oral antiplatelet pro-drug prescribed to 40 million patients worldwide who are at risk for thrombotic events or receiving percutaneous coronary intervention (PCI). However about a fifth of patients treated with clopidogrel do not respond adequately to the drug. From a cohort of 105 patients on whom we had functional data on clopidogrel response, we used ultra-high throughput sequencing to assay mutations in CYP2C19 and ABCB1, the two genes genetically linked to respond. Testing for mutations in CYP2C19, as recommended by the FDA, only correctly predicted if a patient would respond to clopidogrel 52.4% of the time. Similarly, testing of the ABCB1 gene only correctly foretold response in 51 (48.6%) patients. These results are clinically relevant and suggest that until additional genetic factors are discovered that predict response more completely, functional assays are more appropriate for clinical use.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
Aged
Aryl Hydrocarbon Hydroxylases / genetics
Blood Platelets / physiology
Case-Control Studies
Clopidogrel
Coronary Artery Bypass*
Cytochrome P-450 CYP2C19
DNA Mutational Analysis / methods*
Drug Resistance / genetics
Female
Genetic Association Studies
Heart Diseases / blood
Heart Diseases / therapy
Humans
Male
Middle Aged
Mutation
Platelet Aggregation / drug effects
Platelet Aggregation / genetics
Platelet Aggregation Inhibitors / pharmacology*
Platelet Aggregation Inhibitors / therapeutic use
Platelet Function Tests
Ticlopidine / analogs & derivatives*
Ticlopidine / pharmacology
Ticlopidine / therapeutic use

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
Platelet Aggregation Inhibitors
Clopidogrel
Aryl Hydrocarbon Hydroxylases
CYP2C19 protein, human
Cytochrome P-450 CYP2C19
Ticlopidine

Abstract

MeSH terms

Substances

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