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Genetic determinants of warfarin maintenance dose and time in therapeutic treatment range: a RE-LY genomics substudy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 17, no 13, 1425-1439 p.Article in journal (Refereed) Published
Abstract [en]

Aims: We investigated associations between genetic variation in candidate genes and on a genome-wide scale with warfarin maintenance dose, time in therapeutic range (TTR), and risk of major bleeding. Materials & methods: In total, 982 warfarin-treated patients from the RE-LY trial were studied. Results: After adjusting for SNPs in VKORC1 and CYP2C9, SNPs in DDHD1 (rs17126068) and NEDD4 (rs2288344) were associated with dose. Adding these SNPs and CYP4F2 (rs2108622) to a base model increased R-2 by 2.9%. An SNP in ASPH (rs4379440) was associated with TTR (-6.8% per minor allele). VKORC1 was associated with time less than INR 2.0. VKORC1 and CYP2C9 were associated with time more than INR 3.0, but not with major bleeding. Conclusions: We identified two novel genes associated with warfarin maintenance dose and one gene associated with TTR. These genes need to be replicated in an independent cohort.

Place, publisher, year, edition, pages
2016. Vol. 17, no 13, 1425-1439 p.
Keyword [en]
CYP2C9, CYP4F2, genome-wide association study, prediction models, time in therapeutic range, VKORC1, warfarin, warfarin dose
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-304436DOI: 10.2217/pgs-2016-0061ISI: 000382319300006PubMedID: 27488176OAI: oai:DiVA.org:uu-304436DiVA: diva2:1033121
Funder
Swedish Heart Lung FoundationSwedish Research Council, 20120557 20140291Knut and Alice Wallenberg FoundationAstraZenecaGlaxoSmithKline (GSK)
Available from: 2016-10-05 Created: 2016-10-05 Last updated: 2017-11-30Bibliographically approved

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Eriksson, NiclasWallentin, LarsBerglund, LarsAxelsson, TomasOldgren, JonasSiegbahn, AgnetaSyvänen, Ann-ChristineWadelius, ClaesWadelius, Mia
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