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(Stroke. 2005;36:1394.)
© 2005 American Heart Association, Inc.

Original Contributions

Association of a Functional Polymorphism in the Clopidogrel Target Receptor Gene, P2Y12, and the Risk for Ischemic Cerebrovascular Events in Patients With Peripheral Artery Disease

Sophie Ziegler, MD; Martin Schillinger, MD; Marion Funk, MD; Katharina Felber, MD; Markus Exner, MD; Wolfgang Mlekusch, MD; Schila Sabeti, MD; Jasmin Amighi, MD; Erich Minar, MD; Martin Brunner, MD; Markus Müller, MD Christine Mannhalter, PhD

From the Department of Internal Medicine II (S.Z., M.S., W.M., S.S., J.A., E.M.), Division of Angiology and Clinical Pharmacology (S.Z., M.B., M.M.), and Medical and Chemical Laboratory Diagnostics (M.F., K.F., M.E., C.M.), Vienna General Hospital, Medical University of Vienna, Austria.

Correspondence to Sophie Ziegler, MD, Medical University of Vienna, Department of Clinical Pharmacology, Waehringer-Guertel 18-20, 1090 Vienna, Austria. E-mail sophie.ziegler{at}meduniwien.ac.at

Background and Purpose— There is considerable variability in the antiplatelet effects of the thienopyridine agent "clopidogrel." We tested for an association of gene sequence variations in P2Y12 and occurrence of neurological adverse events in patients with symptomatic peripheral artery disease (PAD) during clopidogrel treatment.

Methods— We studied 137 patients undergoing antiplatelet therapy with clopidogrel and 336 patients with aspirin for the occurrence of neurological events (ischemic stroke and/or carotid revascularization). Prevalence of 2 previously described exonic polymorphisms of the P2Y12 gene, 34C>T and 52G>T, was determined by polymerase chain reaction.

Results— Genotype frequencies for mutated, heterozygous, and wild-type alleles for the 34C>T and the 52G>T polymorphisms were 9% (n=40), 44% (n=210), and 47% (n=223), and 4% (n=17), 27% (n=127), and 70% (n=329), respectively. During the median follow-up of 21 months, neurological events occurred in 8% of patients. In patients with aspirin therapy, neither polymorphism was associated with neurological events. However, in clopidogrel patients, carriers of at least one 34T allele had a 4.02-fold increased adjusted risk for neurological events compared with carriers of only 34C alleles (95% confidence interval, 1.08 to 14.9). Neither polymorphism was associated with all-cause mortality.

Conclusions— In PAD patients, clopidogrel response variability exists, which may result in increased risk for cerebrovascular events. Sequence alterations of the target receptor gene represent one possible mechanism for clopidogrel failure. Whether identification of the 34C>T polymorphism as a contributor to this process could serve as risk stratification tool, an indicator for higher clopidogrel doses, or the use of alternate agents warrants further investigation.

Key Words: cerebrovascular accident • clopidogrel • ischemia • polymorphism

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