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Blood, 1 April 2004, Vol. 103, No. 7, pp. 2630-2635. Prepublished online as a Blood First Edition Paper on December 4, 2003; DOI 10.1182/blood-2003-09-3043. This Article Full Text (PDF) All Versions of this Article: 2003-09-3043v1 103/7/2630    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shikata, E. Articles by Otsubo, K. Search for Related Content PubMed PubMed Citation Articles by Shikata, E. Articles by Otsubo, K. Related Collections Related Article in Blood Online Related Letter in Blood Online Social Bookmarking                   What's this? Submitted September 4, 2003 Accepted November 21, 2003 Association of pharmacokinetic (CYP2C9) and pharmacodynamic (vitamin K-dependent protein-Factors II, VII, IX, and X, proteins S and C, and -glutamyl carboxylase) gene variants with warfarin sensitivity Eriko Shikata, Ichiro Ieiri*, Shingo Ishiguro, Hironao Aono, Kazuko Inoue, Tomoko Koide, Shigetsugu Ohgi, and Kenji Otsubo Department of Hospital Pharmacy, Tottrori University, Yonago, Japan Department of Second Surgery, Tottori University, Yonago, Japan * Corresponding author; email: ieiri{at}grape.med.tottori-u.ac.jp. We analyzed mutations of seven vitamin K-dependent protein and cytochrome P450 2C9 genes in 45 patients, and investigated whether any contribute to the large inter-patient variability in the warfarin dose-effect relationship. Total clearance and daily dose, INR and INR/Cp, were used as pharmacokinetic and pharmacodynamic indexes, respectively. Patients were grouped by genotype based on a single polymorphism and combinations of polymorphisms. Among the 30 sequence variants identified, CYP2C9*3, 165Thr>Met of the factor II gene, -402G>A, (37-bp repeat)n, and -746T>C of the factor VII gene, and (CAA repeat)n of the -glutamyl carboxylase gene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses were observed in patients homozygous for the 165Met, -402G, (37-bp repeat)6, and -746T alleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with -402G>A, (CAA repeat)n, CYP2C9*3, and 165Thr>Met, which accounted for 50% of variance. These results suggest that part of the considerable inter-patient variation is attributable to genetic variation, and the combined genotyping of CYP2C9 and certain vitamin K-dependent protein genes is useful for predicting anticoagulant responses. 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