Effect of Genetic Variability in the CYP4F2, CYP4F11, and CYP4F12 Genes on Liver mRNA Levels and Warfarin Response

Abstract

Genetic polymorphisms in the gene encoding cytochrome P450 (CYP) 4F2, a vitamin K oxidase, affect stable warfarin dose requirements and time to therapeutic INR. <i>CYP4F2</i> is part of the <i>CYP4F</i> 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 <i>CYP4F</i> gene cluster on expression of the individual <i>CYP4F</i> genes and warfarin response. mRNA levels of the <i>CYP4F</i> gene cluster were quantified in human liver samples (<i>n</i> = 149) obtained from a well-characterized liver bank and fine mapping of the <i>CYP4F</i> gene cluster encompassing <i>CYP4F2</i>, <i>CYP4F11</i>, and <i>CYP4F12</i> was performed. Genome-wide association study (GWAS) data from a prospective cohort of warfarin-treated patients (<i>n</i> = 711) was also analyzed for genetic variations across the <i>CYP4F</i> gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between <i>CYP4F</i> genes were explored <i>in silico</i> using publicly available data repositories. We found that SNPs in <i>CYP4F2</i>, <i>CYP4F11</i>, and <i>CYP4F12</i> were associated with mRNA expression in the <i>CYP4F</i> gene cluster. In particular, <i>CYP4F2</i> rs2108622 was associated with increased <i>CYP4F2</i> expression while <i>CYP4F11</i> rs1060467 was associated with decreased <i>CYP4F2</i> expression. Interestingly, these <i>CYP4F2</i> and <i>CYP4F11</i> SNPs showed similar effects with warfarin stable dose where <i>CYP4F11</i> rs1060467 was associated with a reduction in daily warfarin dose requirement (∼1 mg/day, <i>P_c</i> = 0.017), an effect opposite to that previously reported with <i>CYP4F2</i> (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, <i>CYP2C9^∗2</i> rs1799853, <i>CYP2C9^∗3</i> rs1057910, and <i>VKORC1</i> 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 <i>CYP4F</i> gene cluster, the opposing effects between the two SNPs in the <i>CYP4F</i> gene cluster appear to compensate for each other and their effect on warfarin dose requirement is unlikely to be clinically significant.