ABSTRACT
Title
Pharmacogenetic of Warfarin: study on a population of Campania Region
Authors
V. Simeon1, V. Conti1, G. Russomanno1, V. Paribello1, C. Mazzaccara2, MR. Lupone3, A. Cottarelli2, L. Sacchetti2, C. Perricone3, A. Filippelli1
1Department of Experimental Medicine, Second University of Naples
2CEINGE - Advanced Biotechnology Avanzate S.C.aR.L., Naples – Department of Biochemistry and Medical Biotechnology, University of Naples
3Regional Center for coagulation disorder, Santobono Hospital, Naples
1Department of Experimental Medicine, Second University of Naples
2CEINGE - Advanced Biotechnology Avanzate S.C.aR.L., Naples – Department of Biochemistry and Medical Biotechnology, University of Naples
3Regional Center for coagulation disorder, Santobono Hospital, Naples
Abstract
Oral anticoagulation for the prevention and treatment of patients with arterial and venous thromboembolic disorders (atrial fibrillation, cardiac valve replacement) is one of the most frequently used therapies in clinical practice. Warfarin, in particular, is the most commonly prescribed oral anticoagulant.
However, warfarin treatment is problematic, due to its narrow therapeutic range and great interindividual variability in the dose required to achieve a therapeutic international normalized ratio (tINR), measure of anticoagulation status. A correct warfarin dosage is crucial to prevent the occurrence of adverse events, excess dosing leads to hemorrhage and underdosing leads to thrombosis.
Variability in patient response is due to a multitude of factors, environmental and genetic (e.g. concomitant medications, age, body weight, diet and alcohol intake). In the last few years, thanks to numerous papers, it has been showed that a consistent part of this variability depends on variants of two genes, cytochrome P450 2C9 (CYP2C9) and VKORC1. Two common variant alleles of CYP2C9 have been identified, the *2 allele (R144C) and the *3 allele (I359L) cause decreased enzymatic activity of 30% and 80% respectively, leading to warfarin sensitivity and in serious cases bleeding complications. Different common polymorphisms/haplotypes have been more recently identified in the VKORC1 gene and some of them have been found to be associated with the variability in warfarin dose requirements, leading both to warfarin resistance and sensitivity.
In the last years, scientific community is debating on the role and the importance of the cytochrome P450 4F2 (CYP4F2) and his variant rs2108622 (C>T). CYP4F2 is involved in VK1 metabolism, and the polymorphism rs2108622 could affect VK1 oxidase activity. CYP4F2 rs2108622 T carriers are likely to have higher hepatic levels of VK1, and thus require a higher warfarin dose. The effect of CYP4F2 in clinical setting has been assessed in several studies and it was reported that rs2108622 could affect warfarin dose requirement.
Many algorithms have been created to define the dose of warfarin but most of them performed less predictably among patients who required very high doses or very low doses.
We evaluated the association of the main polymorphisms of warfarin pathway (CYP2C9 *2 and*3; VKORC1 -1639 (G>A) and 3730 (G>A), CYP4F2 C>T (V433M)with stable dose in a population of 187 patients recruited in Campania Region. All the genetic frequencies were in Hardy-Weinberg equilibrium. Statistical analysis showed an association of stable dose with CYP2C9 and VKORC1 polymorphisms. CYP2C9 *2 and *3 (*1/*1 32.44 ± 14.7 mg/wk; *1/*2 27.47± 10.16 mg/wk; *1/*3 21.53 ± 9.03 mg/wk; *2/*2 22.69 ± 4.89 mg/wk; *2/*3 9.7± 3.2 mg/wk; *3/*3 6.85 ± 11.52 mg/wk ) and VKORC1 -1639 (GG 37.44 ± 14.06 mg/wk; GA 29.45± 11.72 mg/wk; AA 19.1 ± 8.29 mg/wk) showed a reduction in warfarin dose requirement, whereas VKORC1 3730 (GG 25.20 ± 11.4 mg/wk; GA 32.72± 13.77 mg/wk; AA 35.67 ± 15.06 mg/wk) showed a increment in warfarin dose requirement. CYP4F2 didn’t show a significant association with stable dose, even if there was an increment in warfarin dosage (CC 28.64 ± 13.16 mg/wk; CT 29.14± 13.44 mg/wk; TT 31.68 ± 14.86 mg/wk).
Moreover, we retrospectively evaluated the validity of genetic alghoritms on warfarin dose prediction in our population. We measured mean absolute error, coefficient of determination and percentage of predict patient using different genetic alghoritm set against fixed dose approach and clinical alghoritm. Our data highlighted a better efficacy of genetic alghoritm in predicting warfarin dose requirement.
Understanding the underlying genetics of phenotypes in patients on warfarin therapy could be extremely important to avoid side effects like hemorrhage and thrombosis and it is crucial to improve this knowledge. Given the high-risk for this patient we could expect in the future a genetic-guided warfarin dosing.
However, warfarin treatment is problematic, due to its narrow therapeutic range and great interindividual variability in the dose required to achieve a therapeutic international normalized ratio (tINR), measure of anticoagulation status. A correct warfarin dosage is crucial to prevent the occurrence of adverse events, excess dosing leads to hemorrhage and underdosing leads to thrombosis.
Variability in patient response is due to a multitude of factors, environmental and genetic (e.g. concomitant medications, age, body weight, diet and alcohol intake). In the last few years, thanks to numerous papers, it has been showed that a consistent part of this variability depends on variants of two genes, cytochrome P450 2C9 (CYP2C9) and VKORC1. Two common variant alleles of CYP2C9 have been identified, the *2 allele (R144C) and the *3 allele (I359L) cause decreased enzymatic activity of 30% and 80% respectively, leading to warfarin sensitivity and in serious cases bleeding complications. Different common polymorphisms/haplotypes have been more recently identified in the VKORC1 gene and some of them have been found to be associated with the variability in warfarin dose requirements, leading both to warfarin resistance and sensitivity.
In the last years, scientific community is debating on the role and the importance of the cytochrome P450 4F2 (CYP4F2) and his variant rs2108622 (C>T). CYP4F2 is involved in VK1 metabolism, and the polymorphism rs2108622 could affect VK1 oxidase activity. CYP4F2 rs2108622 T carriers are likely to have higher hepatic levels of VK1, and thus require a higher warfarin dose. The effect of CYP4F2 in clinical setting has been assessed in several studies and it was reported that rs2108622 could affect warfarin dose requirement.
Many algorithms have been created to define the dose of warfarin but most of them performed less predictably among patients who required very high doses or very low doses.
We evaluated the association of the main polymorphisms of warfarin pathway (CYP2C9 *2 and*3; VKORC1 -1639 (G>A) and 3730 (G>A), CYP4F2 C>T (V433M)with stable dose in a population of 187 patients recruited in Campania Region. All the genetic frequencies were in Hardy-Weinberg equilibrium. Statistical analysis showed an association of stable dose with CYP2C9 and VKORC1 polymorphisms. CYP2C9 *2 and *3 (*1/*1 32.44 ± 14.7 mg/wk; *1/*2 27.47± 10.16 mg/wk; *1/*3 21.53 ± 9.03 mg/wk; *2/*2 22.69 ± 4.89 mg/wk; *2/*3 9.7± 3.2 mg/wk; *3/*3 6.85 ± 11.52 mg/wk ) and VKORC1 -1639 (GG 37.44 ± 14.06 mg/wk; GA 29.45± 11.72 mg/wk; AA 19.1 ± 8.29 mg/wk) showed a reduction in warfarin dose requirement, whereas VKORC1 3730 (GG 25.20 ± 11.4 mg/wk; GA 32.72± 13.77 mg/wk; AA 35.67 ± 15.06 mg/wk) showed a increment in warfarin dose requirement. CYP4F2 didn’t show a significant association with stable dose, even if there was an increment in warfarin dosage (CC 28.64 ± 13.16 mg/wk; CT 29.14± 13.44 mg/wk; TT 31.68 ± 14.86 mg/wk).
Moreover, we retrospectively evaluated the validity of genetic alghoritms on warfarin dose prediction in our population. We measured mean absolute error, coefficient of determination and percentage of predict patient using different genetic alghoritm set against fixed dose approach and clinical alghoritm. Our data highlighted a better efficacy of genetic alghoritm in predicting warfarin dose requirement.
Understanding the underlying genetics of phenotypes in patients on warfarin therapy could be extremely important to avoid side effects like hemorrhage and thrombosis and it is crucial to improve this knowledge. Given the high-risk for this patient we could expect in the future a genetic-guided warfarin dosing.