Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium

Verma, Shefali Setia; Bergmeijer, Thomas O; Gong, Li; Reny, Jean-Luc; Lewis, Joshua P; Mitchell, Braxton D; Alexopoulos, Dimitrios; Aradi, Daniel; Altman, Russ B; Bliden, Kevin; Bradford, Yuki; Campo, Gianluca; Chang, Kiyuk; Cleator, John H; Déry, Jean-Pierre; Dridi, Nadia P; Fernandez-Cadenas, Israel; Fontana, Pierre; Gawaz, Meinrad; Geisler, Tobias; Gensini, Gian Franco; Giusti, Betti; Gurbel, Paul A; Hochholzer, Willibald; Holmvang, Lene; Kim, Eun-Young; Kim, Ho-Sook; Marcucci, Rossella; Montaner, Joan; Backman, Joshua D; Pakyz, Ruth E; Roden, Dan M; Schaeffeler, Elke; Schwab, Matthias; Shin, Jae Gook; Siller-Matula, Jolanta M; Ten Berg, Jurriën M; Trenk, Dietmar; Valgimigli, Marco; Wallace, John; Wen, Ming-Shien; Kubo, Michiaki; Lee, Ming Ta Michael; Whaley, Ryan; Winter, Stefan; Klein, Teri E; Shuldiner, Alan R; Ritchie, Marylyn D

doi:10.1002/cpt.1911

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Title		Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium
Authors		Verma, Shefali Setia Bergmeijer, Thomas O Gong, Li Reny, Jean-Luc Lewis, Joshua P Mitchell, Braxton D Alexopoulos, Dimitrios Aradi, Daniel Altman, Russ B Bliden, Kevin Bradford, Yuki Campo, Gianluca Chang, Kiyuk Cleator, John H Déry, Jean-Pierre Dridi, Nadia P Fernandez-Cadenas, Israel Fontana, Pierre Gawaz, Meinrad Geisler, Tobias Gensini, Gian Franco Giusti, Betti Gurbel, Paul A Hochholzer, Willibald Holmvang, Lene Kim, Eun-Young Kim, Ho-Sook Marcucci, Rossella Montaner, Joan Backman, Joshua D Pakyz, Ruth E Roden, Dan M Schaeffeler, Elke Schwab, Matthias Shin, Jae Gook Siller-Matula, Jolanta M Ten Berg, Jurriën M Trenk, Dietmar Valgimigli, Marco Wallace, John Wen, Ming-Shien Kubo, Michiaki Lee, Ming Ta Michael Whaley, Ryan Winter, Stefan Klein, Teri E Shuldiner, Alan R Ritchie, Marylyn D show all authors [1 - 48]
Collaboration		ICPC Investigators
Published in		Clinical pharmacology and therapeutics. 2020, vol. 108, no. 5, p. 1067-1077
Abstract		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 CYP2C192 (P value = 1.67e-33). After correction for CYP2C192 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.
Keywords		Aged — Blood Platelets/drug effects/metabolism — Cardiovascular Diseases/blood/genetics/mortality/prevention & control — Clopidogrel/adverse effects/therapeutic use — Coronary Artery Disease/mortality/therapy — Cytochrome P-450 CYP2C19/genetics/metabolism — Female — Genome-Wide Association Study — Humans — Male — Middle Aged — Percutaneous Coronary Intervention/adverse effects/mortality — Pharmacogenetics — Pharmacogenomic Variants — Platelet Aggregation Inhibitors/adverse effects/therapeutic use — Polymorphism, Single Nucleotide — Risk Assessment — Risk Factors — Treatment Outcome
Identifiers		DOI: 10.1002/cpt.1911 PMID: 32472697
Full text		Article (Published version) (960 Kb) - Free access
Structures		Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département de réadaptation et gériatrie
Research group		Geneva Platelet Group (13)
Citation (ISO format)		VERMA, Shefali Setia et al. Genomewide Association Study of Platelet Reactivity and Cardiovascular Response in Patients Treated With Clopidogrel: A Study by the International Clopidogrel Pharmacogenomics Consortium. In: Clinical Pharmacology and Therapeutics, 2020, vol. 108, n° 5, p. 1067-1077. doi: 10.1002/cpt.1911 https://archive-ouverte.unige.ch/unige:155381