A haplotype of CYP2C9 associated with warfarin sensitivity in mechanical heart valve replacement patients

Abstract

AIMS The objectives of this study were to determine the distribution of CYP2C9 variants in Koreans and investigate their association with warfarin dose requirements in patients who received MHVRs. METHODS All nine exons, intron-exon junction, and promoter region of CYP2C9 were amplified and directly sequenced in 50 healthy normal Koreans. Additional direct DNA sequencing of the CYP2C9 gene was conducted in 36 of the 267 MHVR patients who required low maintenance warfarin doses without carrying CYP2C9*3 and VKORC1 1173T mutations. The effects of CYP2C9 genetics on warfarin maintenance dose were assessed in 267 MHVR patients. RESULTS Thirty-nine single nucleotide polymorphisms (SNPs) including seven previously unidentified SNPs were identified in 50 Koreans by direct DNA sequencing. One of the CYP2C9 haplotypes exhibited an association with warfarin low dose requirement. The adjusted odds ratio for the haplotype between the low dose group and the normal subjects was 2.5 (95% confidence interval 1.05, 6.16). This haplotype consisting of -1565C>T, -1188T>C, IVS3+197G>A, IVS3-334C>T, IVS3-65G>C, IVS4-115A>G, and IVS5-73A>G was found in 15% of 36 MHVR patients who required low warfarin doses, while 4% of 50 normal healthy subjects exhibited this haplotype. One of the SNPs comprising this haplotype, -1565C>T, apparently changed a protein binding pattern as observed in electrophoretic mobility shift assay. CONCLUSION The haplotype including -1565C>T, -1188T>C, IVS3+197G>A, IVS3-334C>T, IVS3-65G>C, IVS4-115A>G, and IVS5-73A>G seems to be associated with low warfarin dose requirement and this haplotype could be considered in the development of a warfarin dose prediction model for Asian populations. © 2010 The British Pharmacological Society.