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CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population

    Paola Borgiani*

    † Author for correspondence

    Department of Biopathology and Diagnostic Imaging, School of Medicine, Tor Vergata University, Rome, Italy

    Center of Pharmaceutical Biotechnologies, School of Medicine, Tor Vergata University, 00133 Rome, Italy.

    ,
    Cinzia Ciccacci*

    Department of Biopathology and Diagnostic Imaging, School of Medicine, Tor Vergata University, Rome, Italy

    *These authors contributed equally to this work

    Search for more papers by this author

    ,
    Vittorio Forte

    Azienda Ospedaliera Policlinico Tor Vergata, Rome, Italy

    Elisabetta Sirianni

    Department of Biopathology and Diagnostic Imaging, School of Medicine, Tor Vergata University, Rome, Italy

    ,
    Lucia Novelli

    Department of Biopathology and Diagnostic Imaging, School of Medicine, Tor Vergata University, Rome, Italy

    ,
    Placido Bramanti

    Irccs Centro Neurolesi ‘Bonino Pulejo’ Messina, Italy

    &
    Giuseppe Novelli

    Department of Biopathology and Diagnostic Imaging, School of Medicine, Tor Vergata University, Rome, Italy

    Center of Pharmaceutical Biotechnologies, School of Medicine, Tor Vergata University, 00133 Rome, Italy.

    Azienda Ospedaliera Policlinico Tor Vergata, Rome, Italy

    Published Online:https://doi.org/10.2217/14622416.10.2.261

    Introduction: It is known that warfarin treatment is problematic, due to its narrow therapeutic range and to the great interindividual variability. Numerous papers have shown the important contribution of CYP2C9 and VKORC1 genetic variants to this variability. Recently, a new SNP within the CYP4F2 gene was found associated with warfarin dose in the USA. Aims: The aim of our work was to replicate this study in the Italian population and to assess the new CYP4F2 variant relative contribution in explaining warfarin dose variability with respect to CYP2C9 and VKORC1 genetic variants together with age and weight. Materials & methods: CYP4F2 rs2108622 genotyping was performed by allelic discrimination assay by TaqMan® technology. Analysis of variance and multiple linear regression analyses were carried out to examine the contribution of genetic and nongenetic factors. Results: Our TT patients require 5.49 mg/day versus 2.93 mg/day of our CC patients. Analysis of variance indicates that about 7% of mean weekly warfarin dose variance is explained by CYP4F2 genotype. Our linear regression model including CYP4F2, CYP2C9 and VKORC1 genetic variants, age and weight, explains 60.5% of the interindividual variability. Conclusion: Our data confirm and strengthen the role of this variant.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    Bibliography

    • Hirsh J, Dalen J, Anderson DR et al.: Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest119(Suppl. 1) S8–S21 (2001).
    • Sconce EA, Khan TI, Wynne HA et al.: The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood106,2329–2333 (2005).
    • Sconce EA, Kamali F: Appraisal of current vitamin K dosing algorithms for the reversal of over-anticoagulation with warfarin: the need for a more tailored dosing regimen. Eur. J. Haematol.77(6),457–462 (2006).▪ One of the first papers to report genotype-based algorithms to calculate warfarin dose.
    • Aquilante CL, Langaee TY, Lopez LM et al.: Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin. Pharmacol. Ther.79(4),291–302 (2006).
    • Yin T, Miyata T: Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 – rationale and perspectives. Thromb. Res.120(1),1–10 (2007).
    • van Aken J, Schmedders M, Feuerstein G, Kollek R: Prospects and limits of pharmacogenetics: the thiopurine methyl transferase (TPMT) experience. Am. J. Pharmacogenomics3(3),149–155 (2003).
    • Rieder MJ, Reiner AP, Gage BF et al.: Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N. Engl. J. Med.352,2285–2293 (2005).▪ First paper to describe the correlation of VKORC1 with warfarin dosing.
    • Veenstra DL, You JH, Rieder MJ et al.: Association of vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet. Genomics15,687–691 (2005).
    • Wadelius M, Chen LY, Downes K et al.: Common VKORC1 and GGCXpolymorphisms associated with warfarin dose. Pharmacogenomics J.5,262–270 (2005).
    • 10  D’Andrea G, D’Ambrosio RL, Di Perna P et al.: A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood105,645–649 (2005).
    • 11  Vecsler M, Loebstein R, Almog S et al.: Combined genetic profiles of components and regulators of the vitamin K-dependent γ-carboxylation system affect individual sensitivity to warfarin. Thromb. Haemost.95,205–111 (2006).
    • 12  Borgiani P, Ciccacci C, Forte V, Romano S, Federici G, Novelli G: Allelic variants in the CYP2C9 and VKORC1 loci and interindividual variability in the anticoagulant dose effect of warfarin in Italians. Pharmacogenomics8(11),1545–1550 (2007).▪ A previous paper in the same central Italian population describing a multiple linear regression model including VKORC1 and CYP2C9.
    • 13  Wu AH, Wang P, Smith A et al.: Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations. Pharmacogenomics9(2),169–178 (2008).
    • 14  Schwarz UI, Ritchie MD, Bradford Y et al.: Genetic determinants of response to warfarin during initial anticoagulation. N. Engl. J. Med.358(10),999–1008 (2008).
    • 15  Flockhart DA, O’Kane D, Williams MS et al.: Testing of CYP2C9, VKORC1 alleles for warfarin use pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet. Med.10(2),139–150 (2008).
    • 16  Carlquist JF, Horne BD, Muhlestein JB et al.: Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J. Thromb. Thrombolysis22(3),191–197 (2006).
    • 17  Geisen C, Watzka M, Sittinger K et al: VKORC1 haplotypes and their impact on the inter-individual and inter-ethnical variability of oral anticoagulation. Thromb. Haemost.94(4),773–779 (2005).
    • 18  Yuan HY, Chen JJ, Lee MT et al.: A novel functional VKORC1 promoter polymorphism is associated with inter-individual and interethnic differences in warfarin sensitivity. Hum. Mol. Genet.14,1745–1751 (2005).
    • 19  Caldwell MD, Awad T, Johnson JA et al.: CYP4F2 genetic variant alters required warfarin dose. Blood111(8),4106–4112 (2008).▪▪ First paper to describe the contribution of CYP4F2 genetic variant rs2108622 to the warfarin dosing.
    • 20  Cooper GM, Johnson JA, Langaee TY et al.: A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood112(4),1022–1027 (2008).
    • 21  Novelli G, Ciccacci C, Borgiani P, Papaluca-Amati M, Abadie E: Genetic tests and genomic biomarkers: regulation, qualification and validation. Clinical Cases in Mineral and Bone Metabolism5(2),149–154 (2008).
    • 101  US FDA News www.fda.gov/bbs/topics/NEWS/2007/NEW01684.html