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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. CYP4F2 is part of the CYP4F 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 CYP4F gene cluster on expression of the individual CYP4F genes and warfarin response. mRNA levels of the CYP4F gene cluster were quantified in human liver samples (n = 149) obtained from a well-characterized liver bank and fine mapping of the CYP4F gene cluster encompassing CYP4F2, CYP4F11, and CYP4F12 was performed. Genome-wide association study (GWAS) data from a prospective cohort of warfarin-treated patients (n = 711) was also analyzed for genetic variations across the CYP4F gene cluster. In addition, SNP-gene expression in human liver tissues and interactions between CYP4F genes were explored in silico using publicly available data repositories. We found that SNPs in CYP4F2, CYP4F11, and CYP4F12 were associated with mRNA expression in the CYP4F gene cluster. In particular, CYP4F2 rs2108622 was associated with increased CYP4F2 expression while CYP4F11 rs1060467 was associated with decreased CYP4F2 expression. Interestingly, these CYP4F2 and CYP4F11 SNPs showed similar effects with warfarin stable dose where CYP4F11 rs1060467 was associated with a reduction in daily warfarin dose requirement (∼1 mg/day, Pc = 0.017), an effect opposite to that previously reported with CYP4F2 (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, CYP2C9∗2 rs1799853, CYP2C9∗3 rs1057910, and VKORC1 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 CYP4F gene cluster, the opposing effects between the two SNPs in the CYP4F gene cluster appear to compensate for each other and their effect on warfarin dose requirement is unlikely to be clinically significant.
Highlights
The mRNA levels of the four CYP4F genes that were detected by specific probes varied considerably between individuals, ranging from an expression ratio of 2 for CYP4F8 to an expression ratio of 37 for CYP4F12 (Table 1)
Contrary to a previous report (McDonald et al, 2009), we found a significant association between rs2108622 and liver CYP4F2 mRNA expression (Figure 2C), with subjects homozygous for the rs2108622 minor T allele showing greater CYP4F2 expression compared to subjects homozygous for the major C allele (TT = 1.47 ± 0.29, CC = 0.97 ± 0.31, Pc = 1.72 × 10−3, R2 = 12.6%)
We report for the first time that SNPs and extended haplotypes in CYP4F2, CYP4F11, and CYP4F12 affect the mRNA expression levels of CYP4F2, CYP4F11, and CYP4F12 in human liver tissues and that CYP4F11 plays a role in warfarin response
Summary
The CYP4F gene subfamily comprises six members, namely CYP4F2 (Kikuta et al, 1993), CYP4F3 (CYP4F3A and CYP4F3B) (Kikuta et al, 1998), CYP4F8 (Bylund et al, 2000), CYP4F11 (Cui et al, 2000), CYP4F12 (Bylund et al, 2001; Hashizume et al, 2001), and CYP4F22 (Lefevre et al, 2006). CYP4F2, CYP4F3, CYP4F8, CYP4F11, and CYP4F12 reside together on chromosome 19p13.1-2, spanning over 320 kb (Supplementary Figure 1) These five members of the CYP4F subfamily are all expressed in the liver and are known for their roles in the metabolism of both endogenous and exogenous compounds. They are involved in the catabolism of substrates such as arachidonic acid and its oxygenated derivatives (eicosanoids) such as leukotrienes, prostaglandins (PGs), lipoxins, and hydroxyeicosatetraenoic acids (HETEs) (Kikuta et al, 1999; Bylund et al, 2000, 2001; Hashizume et al, 2001, 2002; Kalsotra et al, 2004), and they catalyze the metabolism of many drugs. CYP4F12 has been reported to be involved in the conversion of the antihistaminic prodrug ebastine to the active drug carebastine by hydroxylation (Hashizume et al, 2001, 2002)
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