TY - JOUR
T1 - Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel
T2 - A Study by the International Clopidogrel Pharmacogenomics Consortium
AU - for the ICPC Investigators
AU - Verma, Shefali Setia
AU - Bergmeijer, Thomas O.
AU - Gong, Li
AU - Reny, Jean Luc
AU - Lewis, Joshua P.
AU - Mitchell, Braxton D.
AU - Alexopoulos, Dimitrios
AU - Aradi, Daniel
AU - Altman, Russ B.
AU - Bliden, Kevin
AU - Bradford, Yuki
AU - Campo, Gianluca
AU - Chang, Kiyuk
AU - Cleator, John H.
AU - Déry, Jean Pierre
AU - Dridi, Nadia P.
AU - Fernandez-Cadenas, Israel
AU - Fontana, Pierre
AU - Gawaz, Meinrad
AU - Geisler, Tobias
AU - Gensini, Gian Franco
AU - Giusti, Betti
AU - Gurbel, Paul A.
AU - Hochholzer, Willibald
AU - Holmvang, Lene
AU - Kim, Eun Young
AU - Kim, Ho Sook
AU - Marcucci, Rossella
AU - Montaner, Joan
AU - Backman, Joshua D.
AU - Pakyz, Ruth E.
AU - Roden, Dan M.
AU - Schaeffeler, Elke
AU - Schwab, Matthias
AU - Shin, Jae Gook
AU - Siller-Matula, Jolanta M.
AU - ten Berg, Jurriën M.
AU - Trenk, Dietmar
AU - Valgimigli, Marco
AU - Wallace, John
AU - Wen, Ming Shien
AU - Kubo, Michiaki
AU - Lee, Ming Ta Michael
AU - Whaley, Ryan
AU - Winter, Stefan
AU - Klein, Teri E.
AU - Shuldiner, Alan R.
AU - Ritchie, Marylyn D.
N1 - Publisher Copyright:
© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85087722297
U2 - 10.1002/cpt.1911
DO - 10.1002/cpt.1911
M3 - Article
C2 - 32472697
AN - SCOPUS:85087722297
SN - 0009-9236
VL - 108
SP - 1067
EP - 1077
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 5
ER -