The GWAS analysis on platelet reactivity and cardiovascular outcome for clopidogrel, the third paper by the International Clopidogrel Pharmacogenomics Consortium (ICPC), has just been published in journal Clinical Pharmacology & Therapeutics.
Clopidogrel is an antiplatelet agent widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Individual responses to clopidogrel show substantial variability, and poor response is often associated with adverse cardiovascular outcomes. Genetic variants in CYP2C19 play an important role in response to clopidogrel. However, loss of function variants in CYP2C19 only account for a small percentage of the overall variation in platelet reactivity, suggesting that novel genetic variants for clopidogrel response remain to be discovered.
The International Clopidogrel Pharmacogenomics Consortium (ICPC) was established to identify genetic factors influencing clopidogrel efficacy and cardiovascular outcomes, using both genome-wide and candidate gene approaches. It comprises 17 study sites from 13 countries that contributed clinical and genetic data for a total of 8,929 patients treated with clopidogrel. Investigators from ICPC performed a GWAS on data from 2,750 individuals of European ancestry. The GWAS analysis showed that CYP2C19*2 is still the strongest genetic determinant of on-clopidogrel platelet reactivity, and no SNP reached genome wide significance for major adverse cardiovascular events (MACE) endpoints. However, in subgroup analyses for patients with coronary artery disease, percutaneous coronary intervention, and acute coronary syndrome, mutations in SCOS5P1, CDC42BPA and CTRAC1 showed genome-wide significance with MACE or stent thrombosis outcomes. This study represents the largest GWAS performed to date for clopidogrel response.
In addition to the GWAS analysis, the ICPC previously published the design paper and results from the candidate gene study, which developed a pharmacogenomic polygenic response score (PgxRS) - based on 31 candidate gene polymorphisms and assessed in 3,391 clopidogrel treated patients from the ICPC. Several variants in CYP2C19, CES1, CYP2C9, CYP2B6 and PEAR1 were identified to have significantly influenced on-clopidogrel platelet reactivity. Patients who carried increasing number of risk alleles that lead to high platelet reactivity were significantly more likely to experience adverse cardiovascular events than patients who carried alleles that lead to better platelet inhibition.
For more information, please refer to the following publications by ICPC:
- Genome-wide association study of platelet reactivity and cardiovascular response in patients treated with clopidogrel: a study by the International Clopidogrel Pharmacogenomics Consortium (ICPC). Clin Pharmacol Ther. 2020 May 30. doi: 10.1002/cpt.1911. PMID: 32472697
- Pharmacogenomic Polygenic Response Score Predicts Ischemic Events and Cardiovascular Mortality in Clopidogrel-Treated Patients. Eur Heart J Cardiovasc Pharmacother. 2019 Sep 3:pvz045. doi:10.1093/ehjcvp/pvz045. PMID: 31504375.
- 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). Am Heart J. 2018 Apr;198:152-159. doi: 10.1016/j.ahj.2017.12.010. PMID: 29653637