title: Mutational analysis clopidogrel resistance and platelet function in patients scheduled for coronary artery bypass grafting.
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.
authors: Department of Biostatistics and Computational Biology and Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors: Mick
authors: M
authors: Correll
authors: Christopher K
authors: CK
authors: Johnson
authors: Giovanni
authors: G
authors: Ferrari
authors: Mariano
authors: M
authors: Brizzio
authors: Andrew W C
authors: AW
authors: Mak
authors: John
authors: J
authors: Quackenbush
authors: Richard E
authors: RE
authors: Shaw
authors: Alex
authors: A
authors: Zapolanski
authors: Juan B
authors: JB
authors: Grau
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001792:Blood Platelets / Q000502:physiology; D016022:Case-Control Studies; D000077144:Clopidogrel; D001026:Coronary Artery Bypass; D065731:Cytochrome P-450 CYP2C19; D004252:DNA Mutational Analysis / Q000379:methods*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D006331:Heart Diseases / Q000097:blood / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010974:Platelet Aggregation / Q000187:drug effects / Q000235:genetics; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010979:Platelet Function Tests; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine