title: Decreased platelet responsiveness to clopidogrel correlates with CYP2C19 and PON1 polymorphisms in atherosclerotic patients.
abstract: Clopidogrel and aspirin are the most commonly used medications worldwide for dual antiplatelet therapy after percutaneous coronary intervention. However, clopidogrel hyporesponsiveness related to gene polymorphisms is a concern. Populations with higher degrees of genetic admixture may have increased prevalence of clopidogrel hyporesponsiveness. To assess this, we genotyped CYP2C19, ABCB1, and PON1 in 187 patients who underwent percutaneous coronary intervention. Race was self-defined by patients. We also performed light transmission aggregometry with adenosine diphosphate (ADP) and arachidonic acid during dual antiplatelet therapy. We found a significant difference for presence of the CYP2C19*2 polymorphism between white and non-white patients. Although 7% of patients had platelet resistance to clopidogrel, this did not correlate with any of the tested genetic polymorphisms. We did not find platelet resistance to aspirin in this cohort. Multivariate analysis showed that patients with PON1 and CYP2C19 polymorphisms had higher light transmission after ADP aggregometry than patients with native alleles. There was no preponderance of any race in patients with higher light transmission aggregometry. In brief, PON1 and CYP2C19 polymorphisms were associated with lower clopidogrel responsiveness in this sample. Despite differences in CYP2C19 polymorphisms across white and non-white patients, genetic admixture by itself was not able to identify clopidogrel hyporesponsiveness.
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: J F M
authors.initials: JF
authors.lastname: Marchini
authors.affiliation: Departamento de Odontologia, Universidade de Uberaba, Uberaba, MG, Brasil.
authors.forename: M R
authors.initials: MR
authors.lastname: Pinto
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: G C
authors.initials: GC
authors.lastname: Novaes
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: A V
authors.initials: AV
authors.lastname: Badran
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: R B
authors.initials: RB
authors.lastname: Pavão
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: G L
authors.initials: GL
authors.lastname: Figueiredo
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: I M
authors.initials: IM
authors.lastname: Lago
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: M O
authors.initials: MO
authors.lastname: Lima-Filho
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: D C
authors.initials: DC
authors.lastname: Lemos
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: M
authors.initials: M
authors.lastname: Tonani
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: C M
authors.initials: CM
authors.lastname: Antloga
authors.affiliation: Divisão de Hematologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: L
authors.initials: L
authors.lastname: Oliveira
authors.affiliation: Departamento de Genética, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: J C
authors.initials: JC
authors.lastname: Lorenzi
authors.affiliation: Unidade de Hemodinâmica e Cardiologia Intervencionista, Divisão de Cardiologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.
authors.forename: J A
authors.initials: JA
authors.lastname: Marin-Neto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000483:Alleles; D043303:Aryldialkylphosphatase / Q000235:genetics; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D000077144:Clopidogrel; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D013988:Ticlopidine; D001241:Aspirin
keywords: Platelet function tests; Single nucleotide polymorphism; Percutaneous coronary intervention; Aspirin; Clopidogrel