Effects of CYP4F2 genetic polymorphisms and haplotypes on clinical outcomes in patients initiated on warfarin therapy.

Background: A variant in the CYP4F2 gene, rs2108622, has been recently shown to determine stable warfarin dose requirements. CYP4F2 has also been shown recently to metabolize vitamin K.

Methods: Three hundred and eleven patients were recruited prospectively from two UK hospitals and followed-up for 6 months. Fine mapping of the whole CYP4F2 region was performed to try and define the haplotype structure of CYP4F2. Genotyping was performed on the Sequenom platform. Univariate and multiple regression analyses were undertaken to assess the effect of CYP4F2 on predefined clinical outcomes of warfarin response.

Results: Fifty-nine single nucleotide polymorphisms in the CYP4F2 gene were analyzed. There was a high degree of linkage disequilibrium in the gene with two haplotype blocks. No association was found with warfarin stable dose and rs2108622 in our prospective cohort of patients even after adjustments to reduce patient heterogeneity. Interestingly, a single nucleotide polymorphism (rs2189784), which is in strong linkage disequilibrium with rs2108622, showed an association with time-to-therapeutic international normalized ratio which remained significant after the correction for multiple testing (Pc = 0.03). No association was shown with the haplotypes after false discovery rate correction.

Conclusion: Although we were unable to demonstrate an association between rs2108622 and stable warfarin dose, our finding of an association between rs2189784 and time-to-therapeutic international normalized ratio is consistent with the recent finding that CYP4F2 plays a role in vitamin K metabolism. However, the effect of CYP4F2 is relatively small in all studies undertaken so far, and thus seems unlikely to be of clinical relevance.