Genomewide Association Study Of Platelet Reactivity And Cardiovascular Response In Patients Treated With Clopidogrel: A Study By The International Clopidogrel Pharmacogenomics Consortium

Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes.CYP2C19loss-of-function alleles play an important role in this response, but account for only a small proportion of variability in response to clopidogrel. An aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify other genetic determinants of clopidogrel pharmacodynamics and clinical response. A genomewide association study (GWAS) was performed using DNA from 2,750 European ancestry individuals, using adenosine diphosphate-induced platelet reactivity and major cardiovascular and cerebrovascular events as outcome parameters. GWAS for platelet reactivity revealed a strong signal forCYP2C19*2(Pvalue = 1.67e-33). After correction forCYP2C19*2no other single-nucleotide polymorphism reached genomewide significance. GWAS for a combined clinical end point of cardiovascular death, myocardial infarction, or stroke (5.0% event rate), or a combined end point of cardiovascular death or myocardial infarction (4.7% event rate) showed no significant results, although in coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome subgroups, mutations inSCOS5P1,CDC42BPA, andCTRAC1showed genomewide significance (lowestPvalues: 1.07e-09, 4.53e-08, and 2.60e-10, respectively).CYP2C19*2is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.