Περίληψη:
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.
Συγγραφείς:
Verma, S.S.
Bergmeijer, T.O.
Gong, L.
Reny, J.-L.
Lewis, J.P.
Mitchell, B.D.
Alexopoulos, D.
Aradi, D.
Altman, R.B.
Bliden, K.
Bradford, Y.
Campo, G.
Chang, K.
Cleator, J.H.
Déry, J.-P.
Dridi, N.P.
Fernandez-Cadenas, I.
Fontana, P.
Gawaz, M.
Geisler, T.
Gensini, G.F.
Giusti, B.
Gurbel, P.A.
Hochholzer, W.
Holmvang, L.
Kim, E.-Y.
Kim, H.-S.
Marcucci, R.
Montaner, J.
Backman, J.D.
Pakyz, R.E.
Roden, D.M.
Schaeffeler, E.
Schwab, M.
Shin, J.G.
Siller-Matula, J.M.
ten Berg, J.M.
Trenk, D.
Valgimigli, M.
Wallace, J.
Wen, M.-S.
Kubo, M.
Lee, M.T.M.
Whaley, R.
Winter, S.
Klein, T.E.
Shuldiner, A.R.
Ritchie, M.D.
for the ICPC Investigators
Λέξεις-κλειδιά:
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
