Contribution of exome sequencing to the identification of genes involved in the response to clopidogrel in cardiovascular patients.
clopidogrel
drug response
exome sequencing
network analysis
platelet reactivity
Journal
Journal of thrombosis and haemostasis : JTH
ISSN: 1538-7836
Titre abrégé: J Thromb Haemost
Pays: England
ID NLM: 101170508
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
05
10
2019
revised:
06
02
2020
accepted:
14
02
2020
pubmed:
23
2
2020
medline:
15
5
2021
entrez:
21
2
2020
Statut:
ppublish
Résumé
On-clopidogrel platelet reactivity (PR) is associated with the risk of thrombotic or bleeding event in selected populations of high-risk patients. PR is a highly heritable phenotype and a few variants of cytochrome genes, essentially CYP2C19, are associated with PR but only explain 5% to 12% of the variability. The aim of this study is to delineate genetic determinants of on-clopidogrel PR using high-throughput sequencing. We performed a whole exome sequencing of 96 low- and matched high-PR patients in a discovery cohort. Exomes from genes with variants significantly associated with PR were sequenced in 96 low- and matched high-PR patients from an independent replication cohort. We identified 585 variants in 417 genes with an adjusted P value < .05. In the replication cohort, all top variants including CYP2C8, CYP2C18, and CYP2C19 from the discovery population were found again. An original network analysis identified several candidate genes of potential interest such as a regulator of PI3K, a key actor in the downstream signaling pathway of the P2Y This study emphasizes the role of CYP-related genes as major regulators of clopidogrel response, including the poorly investigated CYP2C8 and CYP2C18.
Sections du résumé
BACKGROUND
On-clopidogrel platelet reactivity (PR) is associated with the risk of thrombotic or bleeding event in selected populations of high-risk patients. PR is a highly heritable phenotype and a few variants of cytochrome genes, essentially CYP2C19, are associated with PR but only explain 5% to 12% of the variability.
OBJECTIVE
The aim of this study is to delineate genetic determinants of on-clopidogrel PR using high-throughput sequencing.
METHODS
We performed a whole exome sequencing of 96 low- and matched high-PR patients in a discovery cohort. Exomes from genes with variants significantly associated with PR were sequenced in 96 low- and matched high-PR patients from an independent replication cohort.
RESULTS
We identified 585 variants in 417 genes with an adjusted P value < .05. In the replication cohort, all top variants including CYP2C8, CYP2C18, and CYP2C19 from the discovery population were found again. An original network analysis identified several candidate genes of potential interest such as a regulator of PI3K, a key actor in the downstream signaling pathway of the P2Y
CONCLUSION
This study emphasizes the role of CYP-related genes as major regulators of clopidogrel response, including the poorly investigated CYP2C8 and CYP2C18.
Identifiants
pubmed: 32077582
doi: 10.1111/jth.14776
pii: S1538-7836(22)01417-9
doi:
Substances chimiques
Platelet Aggregation Inhibitors
0
Clopidogrel
A74586SNO7
Cytochrome P-450 CYP2C19
EC 1.14.14.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1425-1434Informations de copyright
© 2020 International Society on Thrombosis and Haemostasis.
Références
Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: the Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018; 39: 213-260.
Reny JL, Fontana P, Hochholzer W, et al. Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data. Thromb Haemost. 2016; 115: 844-855.
Fontana P, Berdague P, Castelli C, et al. Clinical predictors of dual aspirin and clopidogrel poor responsiveness in stable cardiovascular patients from the ADRIE study. J Thromb Haemost. 2010; 8: 2614-2623.
Geisler T, Grass D, Bigalke B, et al. The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) score. J Thromb Haemost. 2008; 6: 54-61.
Bray PF, Mathias RA, Faraday N, et al. Heritability of platelet function in families with premature coronary artery disease. J Thromb Haemost. 2007; 5: 1617-1623.
Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. 2009; 302: 849-857.
Fontana P, Cattaneo M, Combescure C, Reny JL. Tailored thienopyridine therapy: no urgency for CYP2C19 genotyping. J Am Heart Assoc. 2013; 2: e000131.
Sibbing D, Aradi D, Alexopoulos D, et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019; 12: 1521-1537.
Claassens DMF, Vos GJA, Bergmeijer TO, et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med. 2019;381:1621-1631.
Scott SA, Collet JP, Baber U, et al. Exome sequencing of extreme clopidogrel response phenotypes identifies B4GALT2 as a determinant of on-treatment platelet reactivity. Clin Pharmacol Ther. 2016; 100: 287-294.
Reny JL, Berdague P, Poncet A, et al. Antiplatelet drug response status does not predict recurrent ischemic events in stable cardiovascular patients: results of the antiplatelet drug resistances and ischemic events study. Circulation. 2012; 125: 3201-3210.
Cuisset T, Grosdidier C, Loundou AD, et al. Clinical implications of very low on-treatment platelet reactivity in patients treated with thienopyridine: the POBA study (predictor of bleedings with antiplatelet drugs). JACC Cardiovasc Interv. 2013; 6: 854-863.
Mani H, Toennes SW, Linnemann B, et al. Determination of clopidogrel main metabolite in plasma: a useful tool for monitoring therapy? Ther Drug Monit. 2008; 30: 84-89.
Savu SN, Silvestro L, Surmeian M, et al. Evaluation of clopidogrel conjugation metabolism: PK studies in man and mice of clopidogrel acyl glucuronide. Drug Metab Dispos. 2016; 44: 1490-1497.
Marsousi N, Daali Y, Fontana P, et al. Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. Clin Pharmacokinet. 2018; 57(10): 1347-1354.
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25: 1754-1760.
Li H, Handsaker B, Wysoker A, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009; 25: 2078-2079.
DePristo MA, Banks E, Poplin R, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011; 43: 491-498.
Jombart T, Ahmed I. adegenet 1.3-1: new tools for the analysis of genome-wide SNP data. Bioinformatics. 2011; 27: 3070-3071.
Tominaga K, Johmura Y, Nishizuka M, Imagawa M. Fad24, a mammalian homolog of Noc3p, is a positive regulator in adipocyte differentiation. J Cell Sci. 2004; 117: 6217-6226.
Kunicki TJ, Nugent DJ. The genetics of normal platelet reactivity. Blood. 2010; 116: 2627-2634.
Trenk D, Hochholzer W. Genetics of platelet inhibitor treatment. Br J Clin Pharmacol. 2014; 77: 642-653.
Cho J, Mosher DF. Role of fibronectin assembly in platelet thrombus formation. J Thromb Haemost. 2006; 4: 1461-1469.
Unsworth AJ, Kriek N, Bye AP, et al. PPARgamma agonists negatively regulate alphaIIbbeta3 integrin outside-in signaling and platelet function through up-regulation of protein kinase A activity. J Thromb Haemost. 2017; 15: 356-369.
Li Z, Ajdic J, Eigenthaler M, Du X. A predominant role for cAMP-dependent protein kinase in the cGMP-induced phosphorylation of vasodilator-stimulated phosphoprotein and platelet inhibition in humans. Blood. 2003; 101: 4423-4429.
Gachet C. Antiplatelet drugs: which targets for which treatments? J Thromb Haemost. 2015; 13(Suppl 1): S313-S322.
Ancrenaz V, Daali Y, Fontana P, et al. Impact of genetic polymorphisms and drug-drug interactions on clopidogrel and prasugrel response variability. Curr Drug Metab. 2010; 11: 667-677.
Storelli F, Daali Y, Desmeules J, Reny JL, Fontana P. Pharmacogenomics of oral antithrombotic drugs. Curr Pharm Des. 2016; 22: 1933-1949.
Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010; 38: 92-99.
Norgard NB, Monte SV. Obesity and inflammation and altered clopidogrel pharmacokinetics and pharmacodynamics. Drug Metab Lett. 2017; 11: 3-13.
Reny JL, Bonvini RF, Bonvini JM, Roffi M, Fontana P. Poor responsiveness to antiplatelet drugs in acute coronary syndromes: clinical relevance and management. Cardiovasc Ther. 2012; 30: e41-e50.
Pallet N, Belleville-Rolland T, Savalle A, et al. Beta-1,4-galactosyltransferase 2 c.909C>T gene variant is predictive of on-clopidogrel platelet reactivity. Pharmacogenomics. 2018; 19: 937-945.
Mega JL, Hochholzer W, Frelinger AL 3rd, et al. Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. JAMA. 2011; 306: 2221-2228.