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Genetic Determinant...
Genetic Determinants of Dabigatran Plasma Levels and Their Relation to Bleeding
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Paré, Guillaume (author)
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- Eriksson, Niclas (author)
- Uppsala universitet,Uppsala kliniska forskningscentrum (UCR)
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Lehr, Thorsten (author)
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Connolly, Stuart (author)
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Eikelboom, John (author)
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Ezekowitz, Michael D (author)
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- Axelsson, Tomas (author)
- Uppsala universitet,Molekylär medicin
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Haertter, Sebastian (author)
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- Oldgren, Jonas (author)
- Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Kardiologi
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Reilly, Paul (author)
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- Siegbahn, Agneta (author)
- Uppsala universitet,Koagulation och inflammationsvetenskap
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- Syvänen, Ann-Christine (author)
- Uppsala universitet,Molekylär medicin
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- Wadelius, Claes (author)
- Uppsala universitet,Medicinsk genetik
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- Wadelius, Mia (author)
- Uppsala universitet,Klinisk farmakogenomik och osteoporos
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Zimdahl-Gelling, Heike (author)
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Yusuf, Salim (author)
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- Wallentin, Lars (author)
- Uppsala universitet,Uppsala kliniska forskningscentrum (UCR),Kardiologi
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(creator_code:org_t)
- 2013
- 2013
- English.
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In: Circulation. - 0009-7322 .- 1524-4539. ; 127:13, s. 1404-
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- BackgroundFixed-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 ResultsWe 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.ConclusionsGenome-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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
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- ref (subject category)
- art (subject category)
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- By the author/editor
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Paré, Guillaume
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Eriksson, Niclas
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Lehr, Thorsten
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Connolly, Stuart
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Eikelboom, John
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Ezekowitz, Micha ...
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show more...
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Axelsson, Tomas
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Haertter, Sebast ...
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Oldgren, Jonas
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Reilly, Paul
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Siegbahn, Agneta
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Syvänen, Ann-Chr ...
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Wadelius, Claes
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Wadelius, Mia
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Zimdahl-Gelling, ...
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Yusuf, Salim
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Wallentin, Lars
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
- Articles in the publication
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Circulation
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Uppsala University