Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium.
(Journal Article;Multicenter Study)
Antiplatelet response to clopidogrel shows wide variation, and poor response is correlated with adverse clinical outcomes. CYP2C19 loss-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 for CYP2C19*2 (P value = 1.67e-33). After correction for CYP2C19*2 no 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 in SCOS5P1, CDC42BPA, and CTRAC1 showed genomewide significance (lowest P values: 1.07e-09, 4.53e-08, and 2.60e-10, respectively). CYP2C19*2 is the strongest genetic determinant of on-clopidogrel platelet reactivity. We identified three novel associations in clinical outcome subgroups, suggestive for each of these outcomes.
Verma, SS; Bergmeijer, TO; Gong, L; Reny, J-L; Lewis, JP; Mitchell, BD; Alexopoulos, D; Aradi, D; Altman, RB; Bliden, K; Bradford, Y; Campo, G; Chang, K; Cleator, JH; Déry, J-P; Dridi, NP; Fernandez-Cadenas, I; Fontana, P; Gawaz, M; Geisler, T; Gensini, GF; Giusti, B; Gurbel, PA; Hochholzer, W; Holmvang, L; Kim, E-Y; Kim, H-S; Marcucci, R; Montaner, J; Backman, JD; Pakyz, RE; Roden, DM; Schaeffeler, E; Schwab, M; Shin, JG; Siller-Matula, JM; Ten Berg, JM; Trenk, D; Valgimigli, M; Wallace, J; Wen, M-S; Kubo, M; Lee, MTM; Whaley, R; Winter, S; Klein, TE; Shuldiner, AR; Ritchie, MD; ICPC Investigators,
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