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.