uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Show others and affiliations
2013 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 127, no 13, 1404- p.Article in journal (Refereed) Published
Abstract [en]

Background

Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in prevention of stroke in atrial fibrillation patients compared to warfarin. We hypothesized that genetic variants could contribute to inter-individual variability in blood concentrations of the active metabolite of dabigatran etexilate, and influence the safety and efficacy of dabigatran.

Methods and Results

We successfully conducted a genome-wide association study in 2,944 RE-LY participants. The CES1 SNP rs2244613 was associated with trough concentrations, and the ABCB1 SNP rs4148738 and CES1 SNP rs8192935 were associated with peak concentrations at genome-wide significance (P<9 x 10-8) with a gene-dose effect. Each minor allele of the CES1 SNP rs2244613 was associated with lower trough concentrations (15% decrease per allele, 95%CI 10-19%; P=1.2 x 10-8) and a lower risk of any bleeding (OR=0.67, 95%CI 0.55-0.82; P=7 x 10-5) in dabigatran-treated participants, with a consistent but non-significant lower risk of major bleeding (OR=0.66, 95%CI 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 (HR=0.59, 95%CI 0.46-0.76; P=5.2 x 10-5) in contrast to no difference in noncarriers (HR=0.96, 95%CI 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 CES1 rs2244613 minor allele occurred in 32.8% of patients in RELY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding.

Place, publisher, year, edition, pages
2013. Vol. 127, no 13, 1404- p.
National Category
Medical Biotechnology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-197322DOI: 10.1161/CIRCULATIONAHA.112.001233ISI: 000316948900016PubMedID: 23467860OAI: oai:DiVA.org:uu-197322DiVA: diva2:612542
Note

Clinical Trial Registration Information

ClinicalTrials.gov; Identifier: NCT00262600

Available from: 2013-03-22 Created: 2013-03-22 Last updated: 2017-12-06

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Authority records BETA

Eriksson, NiclasAxelsson, TomasOldgren, JonasSiegbahn, AgnetaSyvänen, Ann-ChristineWadelius, ClaesWadelius, MiaWallentin, Lars

Search in DiVA

By author/editor
Eriksson, NiclasAxelsson, TomasOldgren, JonasSiegbahn, AgnetaSyvänen, Ann-ChristineWadelius, ClaesWadelius, MiaWallentin, Lars
By organisation
UCR-Uppsala Clinical Research CenterMolecular MedicineCardiologyCoagulation and inflammation scienceMedical GeneticsClinical pharmacogenomics and osteoporosis
In the same journal
Circulation
Medical BiotechnologyMedical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 708 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf