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.