Effect of Genetic Variability in the , , and Genes on Liver mRNA Levels and Warfarin Response.

Genetic polymorphisms in the gene encoding cytochrome P450 (CYP) 4F2, a vitamin K oxidase, affect stable warfarin dose requirements and time to therapeutic INR. is part of the gene cluster, which is highly polymorphic and exhibits a high degree of linkage disequilibrium, making it difficult to define causal variants. Our objective was to examine the effect of genetic variability in the gene cluster on expression of the individual genes and warfarin response. mRNA levels of the gene cluster were quantified in human liver samples ( = 149) obtained from a well-characterized liver bank and fine mapping of the gene cluster encompassing , , and was performed. Genome-wide association study (GWAS) data from a prospective cohort of warfarin-treated patients ( = 711) was also analyzed for genetic variations across the gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between genes were explored using publicly available data repositories. We found that SNPs in , , and were associated with mRNA expression in the gene cluster. In particular, rs2108622 was associated with increased expression while rs1060467 was associated with decreased expression. Interestingly, these and SNPs showed similar effects with warfarin stable dose where rs1060467 was associated with a reduction in daily warfarin dose requirement (∼1 mg/day, = 0.017), an effect opposite to that previously reported with (rs2108622). However, inclusion of either or both of these SNPs in a pharmacogenetic algorithm consisting of age, body mass index (BMI), gender, baseline clotting factor II level, rs1799853, rs1057910, and rs9923231 improved warfarin dose variability only by 0.5-0.7% with an improvement in dose prediction accuracy of ∼1-2%. Although there is complex regulation across the gene cluster, the opposing effects between the two SNPs in the gene cluster appear to compensate for each other and their effect on warfarin dose requirement is unlikely to be clinically significant.