Authors: Espen Molden Cecilie Okkenhaug Erik Ekker Solberg
Publish Date: 2010/03/31
Volume: 66, Issue: 5, Pages: 525-530
Abstract
Several studies have linked mutations in the genes encoding cytochrome P450 2C9 CYP2C9 and vitamin K epoxide reductase complex 1 VKORC1 to a reduced warfarin dose requirement and an increased risk of bleeding with warfarin treatment but the implementation of genotyping as routine practice is still controversial The objective of this study was to investigate whether the frequencies of CYP2C9 variant alleles 2 and 3 and VKORC1 haplotypes 2A/B were increased in a population of warfarintreated patients with an excessive INR responseAll patients with INR values 5 detected by routine monitoring at Diakonhjemmet Hospital Oslo Norway between October 2006 and January 2009 were prospectively enrolled in the study n = 131 ‘cases’ A group of patients with normal INR values 2–3 were randomly included as the reference population n = 130 ‘controls’ The frequencies of CYP2C9 variant alleles 2 430C T and 3 1075A C VKORC1 haplotypes 2A 1173G T and 2B 1173G T + 497T G and the respective genotypes were compared between the study groups by chisquare tests odds ratio OR of cases vs controls with 95 confidence intervals CI calculated for the various endpointsAbout two thirds of the patients in the high INR group were in the maintenance phase of the treatment 3 weeks from first warfarin dose to measurement of INR 5 The frequency of CYP2C9 variant alleles sum of 2 and 3 was significantly higher in patients with high INR cases than in the controls OR 16 95 CI 103–252 p = 0036 Observed frequencies for each of the variant alleles were also higher in the cases than in the controls ie 2C93 OR 197 95 CI 091–241 p = 0073 2C92 OR 136 95 CI 088–158 p = 0246 There were no significant differences in VKORC12 haplotype frequencies between the two subgroups but the number of homozygous VKORC12B carriers was significantly higher in cases than in controls OR 272 102–724 p = 0039The presence of CYP2C9 variant alleles and the homozygous VKORC12B genotype was associated with elevated INR values in warfarintreated patients These results support the implementation of genotyping as a tool to identify patients with an increased risk of excessive anticoagulation during warfarin treatment
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