Paraoxonase-1 Q192R Polymorphism and Antiplatelet Effects of Clopidogrel in Patients Undergoing Elective Coronary Stent Placement

• Published in: Circulation. Cardiovascular genetics Vol. 4; no. 4; pp. 429 - 436
• Main Authors: Trenk, Dietmar, Hochholzer, Willibald, Fromm, Martin F, Zolk, Oliver, Valina, Christian M, Stratz, Christian, Neumann, Franz-Josef
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.08.2011; Lippincott Williams & Wilkins
• Subjects: Aryldialkylphosphatase - genetics; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Coronary heart disease; Elective Surgical Procedures; Genotype; Heart; Humans; Medical sciences; Mutation, Missense; Myocarditis. Cardiomyopathies; Platelet Aggregation - drug effects; Platelet Aggregation - genetics; Platelet Aggregation Inhibitors; Platelet Function Tests; Polymorphism, Single Nucleotide; Radiotherapy. Instrumental treatment. Physiotherapy. Reeducation. Rehabilitation, orthophony, crenotherapy. Diet therapy and various other treatments (general aspects); Stents; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; Myocardial infarction; coronary artery disease; Flow cytometry; Purine nucleoside; Variability; Activity; Esterases; Myocardial disease; Stent; Aggregation; Phosphoric triester hydrolases; Gene; Atherosclerosis; Antithrombotic agent; Genetics; Aryldialkylphosphatase; Diphosphates; Human; Endoprosthesis; Adenosine; Typing; Enzyme; Cytochrome P450; Coronary artery; Instrumentation therapy; Genotype; Patient; Method; Gene expression; genetic polymorphisms; Coronary heart disease; Discharge; Antiplatelet agent; Protein; platelets; Platelet; Reactivity; Hydrolases; Clopidogrel; coronary stent; Single nucleotide polymorphism; Technique; Molecular biology; Thienopyridine derivative; Severe
• ISSN: 1942-325X; 1942-3268
• DOI: 10.1161/CIRCGENETICS.111.960112

BACKGROUND—Recently published data indicate that the paraoxonase-1 (PON1) Q192R genotype—and not as previously shown activity of cytochrome P450 (CYP) 2C19—is the major determinant of metabolic bioactivation of clopidogrel and thereby variability of antiplatelet effect of clopidogrel. We sought to investigate whether the PON1 Q192R gene polymorphism affects platelet reactivity in patients undergoing elective coronary stent placement. METHODS AND RESULTS—The study included 760 consecutive patients undergoing elective coronary stent placement after loading with clopidogrel 600 mg. Platelet function was assessed by adenosine diphosphate-induced (ADP 5 and 20 μmol/L) platelet aggregation and by flow-cytometric analysis of platelet surface protein expression before clopidogrel, at the time of coronary stent placement, and before discharge after coronary stent placement. PON1 Q192R genotype [NM_000446.5:c.575A>G single nucleotide polymorphism (rs662)] was analyzed by TaqMan polymerase chain reaction. Residual platelet aggregation (ADP 5 μmol/L) at predischarge was 8.0% (3.0% to 17.0%) [median (interquartile range)] in PON1 QQ192 patients (n=384), 8.0% (3.0% to 15.0%) in PON1 QR192 (n=304), and 11.0% (3.0% to 18.0%) in PON1 RR192 (n=72; P=0.603). By multivariable linear regression, residual platelet aggregation was not associated with PON1 QQ192/QR192 (partial η<0.001, P=0.728) but with CYP2C19*2 loss-of-function allele (partial η=0.045, P<0.001) as well as any CYP2C19*17 gain-of-function allele (partial η=0.012, P=0.004). All other platelet assays also showed no significant association between PON1 Q192R genotype and antiplatelet effect of clopidogrel. The 1-year incidence of death and myocardial infarction did not differ between PON1 Q192R genotypes. CONCLUSIONS—On-treatment platelet reactivity in patients undergoing coronary stent placement after loading with clopidogrel 600 mg was not associated with PON1 Q192R genotype. CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT00457236.