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Effect of genetic variations on ticagrelor plasma levels and clinical outcomes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
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2015 (English)In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no 29, 1901-1912 p.Article in journal (Refereed) Published
Abstract [en]

Aims Ticagrelor, a direct-acting P2Y(12)-receptor antagonist, is rapidly absorbed and partly metabolized to the major metabolite AR-C124910XX (ARC). To identify single-nucleotide polymorphisms (SNPs) associated with pharmacokinetics of ticagrelor and clinical outcomes, we performed a genome-wide association study (GWAS) in patients treated with ticagrelor in the PLATO trial. Methods and results A two-stage design was used for the GWAS with discovery (discovery phase: n = 1812) and replication cohorts (replication phase: n = 1941). The steady-state area under the curve (AUCss) values, estimated by the population pharmacokinetic (PK) models, were log transformed and analysed on a genome-wide scale using linear regression. SNPs were analysed against clinical events using Cox-regression in 4990 patients. An SNP (rs113681054) in SLCO1B1 was associated with levels of ticagrelor (P = 1.1 x 10(-6)) and ARC (P = 4.6 x 10(-13)). This SNP is in linkage disequilibrium with a functional variant (rs4149056) that results in decreased OATP1B1 transporter activity. Ticagrelor levels were also associated with two independent SNPs (rs62471956, P = 7.7 x 10(-15) and rs56324128, P = 9.7 x 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 x 10(-14)) in UGT2B7. At all loci, the effects were small. None of the identified SNPs that affected ticagrelor PK were associated with the primary composite outcome (cardiovascular death myocardial infarction, and stroke), non-CABG-related bleeds or investigator-reported dyspnoea. Conclusion In patients with ACS, ticagrelor pharmacokinetics is influenced by three genetic loci (SLCO1B1, UGT2B7, and CYP3A4). However, the modest genetic effects on ticagrelor plasma levels did not translate into any detectable effect on efficacy or safety during ticagrelor treatment.

Place, publisher, year, edition, pages
2015. Vol. 36, no 29, 1901-1912 p.
Keyword [en]
Genome-wide association study, Acute Coronary Syndrome, Antiplatelet Treatment, Clopidogrel, Ticagrelor, Pharmacogenetics
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-261970DOI: 10.1093/eurheartj/ehv116ISI: 000359669800010PubMedID: 25935875OAI: oai:DiVA.org:uu-261970DiVA: diva2:853557
Funder
Swedish Heart Lung FoundationAstraZeneca
Available from: 2015-09-14 Created: 2015-09-07 Last updated: 2017-12-04Bibliographically approved

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Varenhorst, ChristophEriksson, NiclasJohansson, ÅsaHagström, EmilÅkerblom, AxelSyvänen, Ann-ChristineJames, Stefan K.Siegbahn, AgnetaWallentin, Lars

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Varenhorst, ChristophEriksson, NiclasJohansson, ÅsaHagström, EmilÅkerblom, AxelSyvänen, Ann-ChristineJames, Stefan K.Siegbahn, AgnetaWallentin, Lars
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UCR-Uppsala Clinical Research CenterMedicinsk genetik och genomikCardiologyEndocrine SurgeryMolecular MedicineCoagulation and inflammation science
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European Heart Journal
Cardiac and Cardiovascular Systems

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