Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism.

Abstract

Objectives: To assess whether CYP2C9 alleles other than CYP2C9*2 and *3 are associated with a low-warfarin dose requirement and the relevance of upstream CYP2C9 polymorphisms to dose requirement and metabolism.

Methods: CYP2C9 exons, intron-exon boundaries and 3 kb of upstream sequence in 20 patients requiring

Results: Polymorphisms at eight different upstream sites were found, five of which were already described. We found that the majority of the upstream polymorphisms were in complete linkage disequilibrium with previously described coding region polymorphisms. However, two polymorphisms, T-1188C and the novel DeltaG-2664DeltaT-2665, occurred both in individuals who were otherwise wild-type and in individuals positive for coding region polymorphisms. Evidence for 11 haplotypes, including 8 with frequencies >or= 0.01, was obtained. In individuals negative for coding region polymorphisms, neither individual genotypes for T-1188C or DeltaG-2664DeltaT-2665 or particular combinations of haplotype pairs were predictive of dose requirement or S-warfarin total clearance, suggesting neither upstream polymorphism was functionally significant. Dose requirements in CYP2C9*11 heterozygotes were not statistically significantly different from homozygous wild-type individuals.

Conclusions: The coding region non-synonymous polymorphisms associated with the CYP2C9*2 and CYP2C9*3 alleles are the major CYP2C9-related factor affecting warfarin dose in UK Caucasians. Upstream CYP2C9 polymorphisms do not appear to be important independent determinants of dose requirement.