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

被引:355
作者
Wadelius, Mia
Chen, Leslie Y.
Eriksson, Niclas
Bumpstead, Suzannah
Ghori, Jilur
Wadelius, Claes
Bentley, David
McGinnis, Ralph
Deloukas, Panos
机构
[1] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England
[2] Univ Uppsala Hosp, Dept Med Sci, S-75185 Uppsala, Sweden
[3] Uppsala Clin Res Ctr, UCR, S-75183 Uppsala, Sweden
[4] Rudbeck Lab, Dept Genet & Pathol, S-75185 Uppsala, Sweden
基金
英国惠康基金;
关键词
D O I
10.1007/s00439-006-0260-8
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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 CYP2C9*2 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 similar 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.
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收藏
页码:23 / 34
页数:12
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