title: Genetic determinants of dabigatran plasma levels and their relation to bleeding.
abstract: BACKGROUND
  Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran.
  
  
  RESULTS
  We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The CES1 single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the ABCB1 single-nucleotide polymorphism rs4148738 and the CES1 single-nucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P<9×10(-8)) with a gene-dose effect. Each minor allele of the CES1 single-nucleotide polymorphism rs2244613 was associated with lower trough concentrations (15% decrease per allele; 95% confidence interval, 10-19; P=1.2×10(-8)) and a lower risk of any bleeding (odds ratio, 0.67; 95% confidence interval, 0.55-0.82; P=7×10(-5)) in dabigatran-treated participants, with a consistent but nonsignificant lower risk of major bleeding (odds ratio, 0.66; 95% confidence interval, 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002), with carriers having less bleeding with dabigatran than warfarin (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P=5.2×10(-)5) in contrast to no difference in noncarriers (hazard ratio, 0.96; 95% confidence interval, 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events.
  
  
  CONCLUSIONS
  Genome-wide association analysis identified that carriage of the CES1 rs2244613 minor allele occurred in 32.8% of patients in RE-LY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.
authors: Population Health Research Institute, Hamilton Health Sciences and McMaster University, David Braley Cardiac Vascular and Stroke Research Institute, 237 Barton St E, Room C3-103, Hamilton, ON, Canada L8L 2X2. pareg@McMaster.ca
authors: Guillaume
authors: G
authors: Paré
authors: Niclas
authors: N
authors: Eriksson
authors: Thorsten
authors: T
authors: Lehr
authors: Stuart
authors: S
authors: Connolly
authors: John
authors: J
authors: Eikelboom
authors: Michael D
authors: MD
authors: Ezekowitz
authors: Tomas
authors: T
authors: Axelsson
authors: Sebastian
authors: S
authors: Haertter
authors: Jonas
authors: J
authors: Oldgren
authors: Paul
authors: P
authors: Reilly
authors: Agneta
authors: A
authors: Siegbahn
authors: Ann-Christine
authors: AC
authors: Syvanen
authors: Claes
authors: C
authors: Wadelius
authors: Mia
authors: M
authors: Wadelius
authors: Heike
authors: H
authors: Zimdahl-Gelling
authors: Salim
authors: S
authors: Yusuf
authors: Lars
authors: L
authors: Wallentin
mesh_terms: D000368:Aged; D000925:Anticoagulants / Q000009:adverse effects / Q000097:blood; D058833:Antithrombin Proteins / Q000009:adverse effects / Q000378:metabolism; D001562:Benzimidazoles / Q000009:adverse effects* / Q000097:blood*; D000069604:Dabigatran; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006470:Hemorrhage / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011355:Prodrugs / Q000009:adverse effects / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects* / Q000097:blood*
chemical_list: D000925:Anticoagulants; D058833:Antithrombin Proteins; D001562:Benzimidazoles; D011355:Prodrugs; D011725:Pyridines; D000069604:Dabigatran