TY - JOUR
TI - Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium
AU - Verma, S.S.
AU - Bergmeijer, T.O.
AU - Gong, L.
AU - Reny, J.-L.
AU - Lewis, J.P.
AU - Mitchell, B.D.
AU - Alexopoulos, D.
AU - Aradi, D.
AU - Altman, R.B.
AU - Bliden, K.
AU - Bradford, Y.
AU - Campo, G.
AU - Chang, K.
AU - Cleator, J.H.
AU - Déry, J.-P.
AU - Dridi, N.P.
AU - Fernandez-Cadenas, I.
AU - Fontana, P.
AU - Gawaz, M.
AU - Geisler, T.
AU - Gensini, G.F.
AU - Giusti, B.
AU - Gurbel, P.A.
AU - Hochholzer, W.
AU - Holmvang, L.
AU - Kim, E.-Y.
AU - Kim, H.-S.
AU - Marcucci, R.
AU - Montaner, J.
AU - Backman, J.D.
AU - Pakyz, R.E.
AU - Roden, D.M.
AU - Schaeffeler, E.
AU - Schwab, M.
AU - Shin, J.G.
AU - Siller-Matula, J.M.
AU - ten Berg, J.M.
AU - Trenk, D.
AU - Valgimigli, M.
AU - Wallace, J.
AU - Wen, M.-S.
AU - Kubo, M.
AU - Lee, M.T.M.
AU - Whaley, R.
AU - Winter, S.
AU - Klein, T.E.
AU - Shuldiner, A.R.
AU - Ritchie, M.D.
AU - for the ICPC Investigators
JO - International Journal of Clinical Pharmacology and Therapeutics
PY - 2020
VL - 108
TODO - 5
SP - 1067-1077
PB - Nature Publishing Group
SN - 0946-1965
TODO - 10.1002/cpt.1911
TODO - adenosine diphosphate;  clopidogrel;  cytochrome P450 2C19;  DNA;  antithrombocytic agent;  clopidogrel;  CYP2C19 protein, human;  cytochrome P450 2C19, acute coronary syndrome;  adult;  allele;  Article;  cardiovascular disease;  cardiovascular response;  cerebrovascular accident;  chromosome;  clinical outcome;  coronary artery disease;  female;  gene locus;  genome-wide association study;  heart infarction;  human;  loading drug dose;  major clinical study;  male;  middle aged;  percutaneous coronary intervention;  pharmacogenomics;  phenotype;  platelet reactivity;  priority journal;  single nucleotide polymorphism;  adverse event;  aged;  blood;  cardiovascular disease;  clinical trial;  coronary artery disease;  drug effect;  genetics;  genome-wide association study;  metabolism;  mortality;  multicenter study;  percutaneous coronary intervention;  pharmacogenetic variant;  pharmacogenetics;  risk assessment;  risk factor;  single nucleotide polymorphism;  thrombocyte;  treatment outcome, Aged;  Blood Platelets;  Cardiovascular Diseases;  Clopidogrel;  Coronary Artery Disease;  Cytochrome P-450 CYP2C19;  Female;  Genome-Wide Association Study;  Humans;  Male;  Middle Aged;  Percutaneous Coronary Intervention;  Pharmacogenetics;  Pharmacogenomic Variants;  Platelet Aggregation Inhibitors;  Polymorphism, Single Nucleotide;  Risk Assessment;  Risk Factors;  Treatment Outcome
TODO - 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. © 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
ER -