Effect of genetic variations on ticagrelor plasma levels and clinical outcomes.

Published

Journal Article

AIMS: Ticagrelor, a direct-acting P2Y12-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 × 10(-6)) and ARC (P = 4.6 × 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 × 10(-15) and rs56324128, P = 9.7 × 10(-12)) in the CYP3A4 region. Further, ARC levels were associated with rs61361928 (P = 3.0 × 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. CLINICAL TRIAL REGISTRATION: NCT00391872.

Full Text

Duke Authors

Cited Authors

  • Varenhorst, C; Eriksson, N; Johansson, Å; Barratt, BJ; Hagström, E; Åkerblom, A; Syvänen, A-C; Becker, RC; James, SK; Katus, HA; Husted, S; Steg, PG; Siegbahn, A; Voora, D; Teng, R; Storey, RF; Wallentin, L; PLATO Investigators,

Published Date

  • August 1, 2015

Published In

Volume / Issue

  • 36 / 29

Start / End Page

  • 1901 - 1912

PubMed ID

  • 25935875

Pubmed Central ID

  • 25935875

Electronic International Standard Serial Number (EISSN)

  • 1522-9645

Digital Object Identifier (DOI)

  • 10.1093/eurheartj/ehv116

Language

  • eng

Conference Location

  • England