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Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
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2013 (Engelska)Ingår i: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 127, nr 13, s. 1404-Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2013. Vol. 127, nr 13, s. 1404-
Nationell ämneskategori
Medicinsk bioteknologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
URN: urn:nbn:se:uu:diva-197322DOI: 10.1161/CIRCULATIONAHA.112.001233ISI: 000316948900016PubMedID: 23467860OAI: oai:DiVA.org:uu-197322DiVA, id: diva2:612542
Anmärkning

Clinical Trial Registration Information

ClinicalTrials.gov; Identifier: NCT00262600

Tillgänglig från: 2013-03-22 Skapad: 2013-03-22 Senast uppdaterad: 2017-12-06

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

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Eriksson, NiclasAxelsson, TomasOldgren, JonasSiegbahn, AgnetaSyvänen, Ann-ChristineWadelius, ClaesWadelius, MiaWallentin, Lars
Av organisationen
Uppsala kliniska forskningscentrum (UCR)Molekylär medicinKardiologiKoagulation och inflammationsvetenskapMedicinsk genetikKlinisk farmakogenomik och osteoporos
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Circulation
Medicinsk bioteknologiMedicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

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