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


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.


CONCLUSIONS
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.


BACKGROUND
NCT00391872.
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.
Christoph
C
Varenhorst
Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds väg 14B, level 1, SE-751 85 Uppsala, Sweden.
Niclas
N
Eriksson
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.
Åsa
Å
Johansson
AstraZeneca R&D, Alderley Park, Cheshire, UK.
Bryan J
BJ
Barratt
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.
Emil
E
Hagström
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.
Axel
A
Åkerblom
Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden.
Ann-Christine
AC
Syvänen
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.
Richard C
RC
Becker
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.
Stefan K
SK
James
Medizinische Klinik, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Hugo A
HA
Katus
Medical Department, Hospital Unit West, Herning/Holstebro, Denmark.
Steen
S
Husted
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.
Ph Gabriel
PG
Steg
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.
Agneta
A
Siegbahn
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Deepak
D
Voora
AstraZeneca LP, Wilmington, DE, USA.
Renli
R
Teng
Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
Robert F
RF
Storey
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.
Lars
L
Wallentin
D054058:Acute Coronary Syndrome / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D058921:Purinergic P2Y Receptor Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D000077486:Ticagrelor; D016896:Treatment Outcome
C561701:AR C124910XX; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D058921:Purinergic P2Y Receptor Antagonists; C503999:SLCO1B1 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000077486:Ticagrelor; D000241:Adenosine
Acute Coronary Syndrome; Antiplatelet Treatment; Clopidogrel; Genome-wide association study; Pharmacogenetics; Ticagrelor