Association of warfarin dose with genes involved in its action and metabolism

We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the na...

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Main Authors:	Wadelius, Mia, Chen, Leslie Y., Eriksson, Niclas, Bumpstead, Suzannah, Ghori, Jilur, Wadelius, Claes, Bentley, David, McGinnis, Ralph, Deloukas, Panos
Format:	Online
Language:	English
Published:	Springer-Verlag 2006
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797064/

id	pubmed-1797064
recordtype	oai_dc
spelling	pubmed-17970642007-02-13 Association of warfarin dose with genes involved in its action and metabolism Wadelius, Mia Chen, Leslie Y. Eriksson, Niclas Bumpstead, Suzannah Ghori, Jilur Wadelius, Claes Bentley, David McGinnis, Ralph Deloukas, Panos Original Investigation We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX and ORM1-ORM2 and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2 and ORM1-ORM2 were associated with dose (P < 0.05). VKORC1, CYP2C9, CYP2C18 and CYP2C19 were significant after experiment-wise correction for multiple testing (P < 0.000175), however, the association of CYP2C18 and CYP2C19 was fully explained by linkage disequilibrium with CYP2C92 and/or 3. PROC and APOE were both significantly associated with dose after correction within each gene. A multiple regression model with VKORC1, CYP2C9, PROC and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to ∼10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin. Springer-Verlag 2006-10-18 2007-03 /pmc/articles/PMC1797064/ /pubmed/17048007 http://dx.doi.org/10.1007/s00439-006-0260-8 Text en © Springer-Verlag 2006
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Wadelius, Mia Chen, Leslie Y. Eriksson, Niclas Bumpstead, Suzannah Ghori, Jilur Wadelius, Claes Bentley, David McGinnis, Ralph Deloukas, Panos
spellingShingle	Wadelius, Mia Chen, Leslie Y. Eriksson, Niclas Bumpstead, Suzannah Ghori, Jilur Wadelius, Claes Bentley, David McGinnis, Ralph Deloukas, Panos Association of warfarin dose with genes involved in its action and metabolism
author_facet	Wadelius, Mia Chen, Leslie Y. Eriksson, Niclas Bumpstead, Suzannah Ghori, Jilur Wadelius, Claes Bentley, David McGinnis, Ralph Deloukas, Panos
author_sort	Wadelius, Mia
title	Association of warfarin dose with genes involved in its action and metabolism
title_short	Association of warfarin dose with genes involved in its action and metabolism
title_full	Association of warfarin dose with genes involved in its action and metabolism
title_fullStr	Association of warfarin dose with genes involved in its action and metabolism
title_full_unstemmed	Association of warfarin dose with genes involved in its action and metabolism
title_sort	association of warfarin dose with genes involved in its action and metabolism
description	We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX and ORM1-ORM2 and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2 and ORM1-ORM2 were associated with dose (P < 0.05). VKORC1, CYP2C9, CYP2C18 and CYP2C19 were significant after experiment-wise correction for multiple testing (P < 0.000175), however, the association of CYP2C18 and CYP2C19 was fully explained by linkage disequilibrium with CYP2C92 and/or 3. PROC and APOE were both significantly associated with dose after correction within each gene. A multiple regression model with VKORC1, CYP2C9, PROC and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to ∼10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin.
publisher	Springer-Verlag
publishDate	2006
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797064/
_version_	1611394275096920064

Association of warfarin dose with genes involved in its action and metabolism

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