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

Publication ,  Journal Article
Varenhorst, C; Eriksson, N; Johansson, Å; Barratt, BJ; Hagström, E; Åkerblom, A; Syvänen, A-C; Becker, RC; James, SK; Katus, HA; Husted, S ...
Published in: Eur Heart J
August 1, 2015

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.

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Published In

Eur Heart J

DOI

EISSN

1522-9645

Publication Date

August 1, 2015

Volume

36

Issue

29

Start / End Page

1901 / 1912

Location

England

Related Subject Headings

  • Treatment Outcome
  • Ticagrelor
  • Purinergic P2Y Receptor Antagonists
  • Polymorphism, Single Nucleotide
  • Organic Anion Transporters
  • Middle Aged
  • Male
  • Liver-Specific Organic Anion Transporter 1
  • Humans
  • Glucuronosyltransferase
 

Citation

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Varenhorst, C., Eriksson, N., Johansson, Å., Barratt, B. J., Hagström, E., Åkerblom, A., … PLATO Investigators, . (2015). Effect of genetic variations on ticagrelor plasma levels and clinical outcomes. Eur Heart J, 36(29), 1901–1912. https://doi.org/10.1093/eurheartj/ehv116
Varenhorst, Christoph, Niclas Eriksson, Åsa Johansson, Bryan J. Barratt, Emil Hagström, Axel Åkerblom, Ann-Christine Syvänen, et al. “Effect of genetic variations on ticagrelor plasma levels and clinical outcomes.Eur Heart J 36, no. 29 (August 1, 2015): 1901–12. https://doi.org/10.1093/eurheartj/ehv116.
Varenhorst C, Eriksson N, Johansson Å, Barratt BJ, Hagström E, Åkerblom A, et al. Effect of genetic variations on ticagrelor plasma levels and clinical outcomes. Eur Heart J. 2015 Aug 1;36(29):1901–12.
Varenhorst, Christoph, et al. “Effect of genetic variations on ticagrelor plasma levels and clinical outcomes.Eur Heart J, vol. 36, no. 29, Aug. 2015, pp. 1901–12. Pubmed, doi:10.1093/eurheartj/ehv116.
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. Effect of genetic variations on ticagrelor plasma levels and clinical outcomes. Eur Heart J. 2015 Aug 1;36(29):1901–1912.
Journal cover image

Published In

Eur Heart J

DOI

EISSN

1522-9645

Publication Date

August 1, 2015

Volume

36

Issue

29

Start / End Page

1901 / 1912

Location

England

Related Subject Headings

  • Treatment Outcome
  • Ticagrelor
  • Purinergic P2Y Receptor Antagonists
  • Polymorphism, Single Nucleotide
  • Organic Anion Transporters
  • Middle Aged
  • Male
  • Liver-Specific Organic Anion Transporter 1
  • Humans
  • Glucuronosyltransferase