Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points—Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

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

doi:10.1016/j.ahj.2017.12.010

Cited by 25 publications

(24 citation statements)

References 56 publications

(46 reference statements)

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“…The ICPC is an international effort led by the Pharmacogenomics Research Network (PGRN) and Pharmacogenomics Knowledgebase (PharmGKB). 20 Based on the data published on www.clini caltr ials.gov as of June 2011, studies with at least 50 clopidogrel-treated patients potentially containing genetic and platelet reactivity data were identified for participation. Lead investigators were invited to share DNA samples, platelet reactivity test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and GWAS.…”

Section: Methodsmentioning

confidence: 99%

“…The prioritization was as follows: VASP assay > VerifyNow P2Y 12 > adenosine diphosphate (ADP)-induced LTA (higher ADP concentration > lower ADP concentration) > other tests. 20 For each subcohort, one platelet function test was chosen based on the highest-ranked assay measured at that site that maximized the sample size. A schematic of this is shown in Figure S1.…”

Section: Methodsmentioning

confidence: 99%

“…Standardization of platelet reactivity phenotypes was performed by calculating a Z-score within each study for use in analyses across studies, as previously reported. 20,22 Each selected variable was then standardized with mean of 0 and SD of 1 while grouping by site and the selected variable. Standardized platelet reactivity was used as a continuous response variable in our GWAS.…”

Section: Methodsmentioning

confidence: 99%

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

Verma

Bergmeijer

Gong

et al. 2020

Clin Pharma and Therapeutics

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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

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Verma

Bergmeijer

Gong

et al. 2020

Clin Pharma and Therapeutics

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“…The second validation cohort consisted of all patients in the genome wide association study (GWAS) subgroup of the International Clopidogrel Pharmacogenomics Consortium (ICPC) database. The aim of the ICPC is to find novel genetic markers which influence clopidogrel efficacy using GWAS and candidate gene approaches, combined with pharmacodynamic and clinical outcome data [ 23 , 24 ]. All clopidogrel-treated patients undergoing elective PCI were selected in whom ADP-stimulated platelet function testing was performed.…”

Section: Methodsmentioning

confidence: 99%

Effect of CYP3A4*22 and PPAR-α Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention

Bergmeijer

Yasmina

Vos

et al. 2020

Genes

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This study aims to determine whether genetic variants that influence CYP3A4 expression are associated with platelet reactivity in clopidogrel-treated patients undergoing elective percutaneous coronary intervention (PCI), and to evaluate the influence of statin/fibrate co-medication on these associations. A study cohort was used containing 1124 consecutive elective PCI patients in whom CYP3A4*22 and PPAR-α (G209A and A208G) SNPs were genotyped and the VerifyNow P2Y12 platelet reactivity test was performed. Minor allele frequencies were 0.4% for CYP3A4*22/*22, 6.8% for PPAR-α G209A AA, and 7.0% for PPAR-α A208G GG. CYP3A4*22 was not associated with platelet reactivity. The PPAR-α genetic variants were significantly associated with platelet reactivity (G209A AA: −24.6 PRU [−44.7, −4.6], p = 0.016; A208G GG: −24.6 PRU [−44.3, −4.8], p = 0.015). Validation of these PPAR-α results in two external cohorts, containing 716 and 882 patients, respectively, showed the same direction of effect, although not statistically significant. Subsequently, meta-analysis of all three cohorts showed statistical significance of both variants in statin/fibrate users (p = 0.04 for PPAR-a G209A and p = 0.03 for A208G), with no difference in statin/fibrate non-users. In conclusion, PPAR-α G209A and A208G were associated with lower platelet reactivity in patients undergoing elective PCI who were treated with clopidogrel and statin/fibrate co-medication. Further research is necessary to confirm these findings.

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“…practice guidelines that can assist providers in applying the results of PGx testing to the management of medications used to treat mood disorders, cardiovascular disease, cancer, or other diseases among adults. 2,3 Previous research in adult populations has demonstrated the clinical utility [4][5][6][7][8] and cost-effectiveness 9,10 for both reactive PGx testing to guide current treatment and pre-emptive testing to guide future treatment decisions. However, the evidence base for PGx testing in pediatric patients and in treatment of diseases prevalent during childhood is less robust.…”

Section: Pharmacogenetic Testing In Childrenmentioning

confidence: 99%

Retrospective Review of Pharmacogenetic Testing at an Academic Children’s Hospital

Roberts

Wagner

Sandritter

et al. 2020

Clinical Translational Sci

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There is limited evidence to support pharmacogenetic (PGx) testing in children. We conducted a retrospective review of PGx testing among 452 patients at an academic children's hospital to determine the potential utility of PGx in diseases of childhood and to identify targets for future pediatric pharmacogenetic research. An actionable gene-drug pair associated with the 28 genes tested (Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B, Pharmacogenomics Knowledge Base (PharmGKB) level 1A or B, or US Food and Drug Administration (FDA) recommendation and a PharmGKB level) was present in 98.7% of patients. We identified 203 actionable gene-drug-diagnosis groups based on the indications for each actionable drug listed in Lexicomp. Among patients with an actionable gene-drug-diagnosis group, 49.3% had a diagnosis where the drug was a therapeutic option and PGx could be used to guide treatment selection. Among patients with an associated diagnosis, 30.9% had a prescription for the actionable drug allowing PGx guided dosing. Three genes (CYP2C19, CYP2D6, and CYP3A5) accounted for all the gene-drug-diagnosis groups with matching diagnoses and prescriptions. The most common gene-drug-diagnosis groups with matching diagnoses and prescriptions were CYP2C19-citalopram-escitalopram-depression 3.3% of patients tested; CYP2C19-dexlansoprazole-gastritis-esophagitis 3.1%; CYP2C19-omeprazole-gastritis-esophagitis 2.4%; CYP2D6-atomoxetine-attention deficit hyperactivity disorder 2.2%; and CYP2C19-citalopram-escitalopram-obsessivecompulsive disorder 1.5%. PGx could be used to guide selection of current treatment options or medication dosing in almost half (48.7%) of pediatric patients tested. Mood disorders and gastritis/esophagitis are promising targets for future study of PGx testing because of the high prevalence of these diagnoses and associated actionable gene-drug pairs in the pediatric population. Pharmacogenetic (PGx) testing, specifically the inquiry into genetic variants in pharmacokinetic or pharmacodynamic pathways involved in medication metabolism or response, is commercially available and being promoted to improve patient outcomes. 1 The level of evidence supporting the clinical utility of testing for variants in individual genes differs, and translation of the test results into clinical practice is complicated. Several organizations, including the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Royal Dutch Association for the Advancement of Pharmacy-Pharmacogenetics Working Group (DPWG), have created detailed, evidence-based, gene-drug clinical

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Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points—Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

Abstract: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.

Cited by 25 publications

References 56 publications

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

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

Effect of CYP3A4*22 and PPAR-α Genetic Variants on Platelet Reactivity in Patients Treated with Clopidogrel and Lipid-Lowering Drugs Undergoing Elective Percutaneous Coronary Intervention

Retrospective Review of Pharmacogenetic Testing at an Academic Children’s Hospital

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