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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)
- Source :
- American Heart Journal, American Heart Journal, Vol. 198 (2018) pp. 152-159, American Heart Journal, Elsevier, 2018, 198, pp.152-159. ⟨10.1016/j.ahj.2017.12.010⟩
- Publication Year :
- 2017
-
Abstract
- RATIONALE: The P2Y(12) receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention or ischemic stroke. Platelet inhibition by clopidogrel shows wide inter-patient variability and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. STUDY DESIGN: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics and cardiovascular outcomes, to perform candidate gene and genome-wide association studies. RESULTS: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate (ADP) stimulated platelet function tests included Vasodilator-Stimulated Phosphoprotein (VASP) assay, Light Transmittance Aggregometry (LTA) and the VerifyNow P2Y(12) assay. A proof of principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (p-value = 5.1×10(−40)). CONCLUSION: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic techniques in a large cohort of clopidogrel-treated patients in order to better understand the genetic basis of on-treatment response variability.
- Subjects :
- Oncology
Male
Candidate gene
[SDV.BIO]Life Sciences [q-bio]/Biotechnology
Internationality
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Genome-wide association study
030204 cardiovascular system & hematology
Cardiovascular Medicine
MESH: Risk Assessment
MESH: Receptors, Purinergic P2Y12
0302 clinical medicine
P2Y12
MESH: Molecular Targeted Therapy
Receptors
Medicine
030212 general & internal medicine
Molecular Targeted Therapy
MESH: Treatment Outcome
MESH: Genetic Association Studies
Cardiology, Cardiovascular Medicine
MESH: Aged
ddc:616
Acute Coronary Syndrome/diagnosis/drug therapy/mortality
MESH: Middle Aged
Purinergic P2Y12/drug effects/genetics
Middle Aged
Clopidogrel
Prognosis
Receptors, Purinergic P2Y12
3. Good health
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Survival Rate
Treatment Outcome
Female
Cardiology and Cardiovascular Medicine
medicine.drug
circulatory and respiratory physiology
Acute coronary syndrome
medicine.medical_specialty
MESH: Survival Rate
Cardiology
MESH: Pharmacogenetics
CYP2C19
Clopidogrel/therapeutic use
Risk Assessment
MESH: Prognosis
Article
NO
03 medical and health sciences
Internal medicine
Humans
cardiovascular diseases
Acute Coronary Syndrome
Genetic Association Studies
Aged
MESH: Humans
business.industry
MESH: Clopidogrel
medicine.disease
Genome-wide association approach, candidate gene approaches, clopidogrel, efficacy, pharmacodynamic, clinical end points, International Clopidogrel Pharmacogenomics Consortium (ICPC), Cardiovascular Medicine
MESH: Acute Coronary Syndrome
MESH: Male
Pharmacogenetics
Pharmacogenomics
MESH: Genome-Wide Association Study
ddc:618.97
MESH: Internationality
business
MESH: Female
Molecular Targeted Therapy/methods
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 10976744 and 00028703
- Volume :
- 198
- Database :
- OpenAIRE
- Journal :
- American heart journal
- Accession number :
- edsair.doi.dedup.....9f3d513bc2b922f707381d003c3eea76