Christoph Varenhorst1, Niclas Eriksson2, Åsa Johansson3, Bryan J Barratt4, Emil Hagström5, Axel Åkerblom5, Ann-Christine Syvänen6, Richard C Becker7, Stefan K James5, Hugo A Katus8, Steen Husted9, Ph Gabriel Steg10, Agneta Siegbahn11, Deepak Voora12, Renli Teng13, Robert F Storey14, Lars Wallentin5. 1. Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, level 1, SE-751 85 Uppsala, Sweden christoph.varenhorst@ucr.uu.se. 2. Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, level 1, SE-751 85 Uppsala, Sweden. 3. Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, level 1, SE-751 85 Uppsala, Sweden Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. 4. AstraZeneca R&D, Alderley Park, Cheshire, UK. 5. Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, level 1, SE-751 85 Uppsala, Sweden. 6. Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden. 7. Division of Cardiovascular Health and Disease, Heart, Lung and Vascular Institute, Academic Health Center, Cincinnati, OH, USA Heart, Lung and Vascular Institute, Cardiovascular Services, University of Cincinnati Health System, Cincinnati, OH, USA. 8. Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany. 9. Medical Department, Hospital Unit West, Herning/Holstebro, Denmark. 10. INSERM-Unité 1148, Paris, France Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Paris, France Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France NHLI Imperial College, ICMS, Royal Brompton Hospital, London, UK. 11. Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, level 1, SE-751 85 Uppsala, Sweden Department of Medical Sciences, Clinical Chemistry, Uppsala University, Uppsala, Sweden. 12. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA. 13. AstraZeneca LP, Wilmington, DE, USA. 14. Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
Abstract
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. Published on behalf of the European Society of Cardiology. All rights reserved.
RCT Entities:
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Huiru Chang; Song Yao; David Tritchler; Meredith A Hullar; Johanna W Lampe; Lilian U Thompson; Susan E McCann Journal: Cancer Epidemiol Biomarkers Prev Date: 2019-02 Impact factor: 4.254