Genotipo de los genes VKORC1 y CYP2C9 en la respuesta individual a la warfarina
Palabras clave:
WARFARINA, ALELOS, GENOTIPO, HEMORRAGIA
Resumen
Introducción: la warfarina es un fármaco ampliamente utilizado como anticoagulante oral. Su estrecho rango terapéutico y marcada variabilidad interindividual en la respuesta requieren un control riguroso en su administración para evitar accidentes hemorrágicos.
Objetivos: correlacionar las variantes genéticas de CYP2C9*2 y *3 y VKORC1 (C1173T) con la respuesta y los efectos adversos.
Material y método: los genotipos CYP2C9*1, *2, *3, y VKORC1 fueron obtenidos por PCR-RFLP y los resultados analizados usando el paquete estadístico SPSS 12.0.
Resultados: hay una tendencia a la reducción de dosis en relación con la presencia de alelos polimórficos. Los portadores de CYP2C9*3 requirieron la menor dosis de mantenimiento, seguidos por los portadores de CYP2C9*2 y homocigotos CYP2C9 *1, en ese orden, (4,4±1,0 vesus 5,4±2,3 versus 7,0±3,6 mg/d, p=0,03). Los portadores CYP2C9*3 tuvieron, además, un aumento del riesgo de sobreanticoagulación y requirieron casi el doble de ajustes de dosis para lograr una adecuada anticoagulación. Para VKORC1, los homocigotas T/T necesitaron la dosis más baja, seguidos por los heterocigotas C/T y homocigotas C/C, en ese orden (3,6±0,6 versus 5,5±0,5 y 7,9±0,7 mg/d, p <0,001). Los pacientes T/T tuvieron un mayor riesgo de sobreanticoagulación que los C/T y C/C. El genotipo T/T de VKORC1 produce en todas las combinaciones con CYP2C9 una disminución cercana a 50% de la dosis diaria de warfarina.
Conclusiones: se confirma una sensibilidad aumentada a la warfarina en pacientes portadores de alelos *2 y *3 de CYP2C9, y T de VKORC1. Se demuestra un efecto combinado (aproximadamente aditivo) de los alelos variantes de ambos genes.
Citas
(1) Go AS, Hylek EM, Chang Y, Phillips KA, Henault LE, Capra AM, et al. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice? JAMA 2003; 290(20): 2685-92.
(2) Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119: 8S-21S.
(3) Weinshilboum R. Inheritance and drug response. N Engl J Med 2003; 348: 529-37.
(4) Evans WE, Relling M. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286: 487-91.
(5) Rettie AE, Tai G. The pharmocogenomics of warfarin: closing in on personalized medicine. Mol Interv 2006; 6: 223-7.
(6) Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnet™ systematic review and meta-analysis. Genet Med 2005; 7(2): 97-104.
(7) Raggio V, Neira P, Esperón P, Lorenzo M, Stoll M. Respuesta terapéutica inadecuada a la warfarina en un paciente genéticamente susceptible. Rev Med Urug 2005; 21: 242-6.
(8) Raggio V, Esperón P, Lorenzo M, Taub I, Cuesta A, Rodríguez A, et al. Variantes de los genes CYP2C9 y apolipoproteína E en la respuesta individual a la warfarina. Rev Urug Cardiol 2006; 21: 104-16.
(9) Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352(22): 2285-93.
(10) D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005; 105(2): 645-9.
(11) XXI Congreso Uruguayo de Cardiología: temas libres. Rev Urug Cardiol 2005; 20(3): 199. Obtenido de: http://www.scielo.edu.uy/scielo.php?script=sci_arttext&pid=S0797-00482005000300007&lng=es&nrm=iso&tlng=es (Consulta: 20 octubre 2008).
(12) Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1. Rationale and perspectives. Thrombosis Research 2007; 120: 1-10.
(13) Estrada N, Sevrini I, Prego A, Giusti M, Azambuja C, Álvarez Rocha A. Prevalencia de los polimorfismos del CYP2C9 en una población uruguaya anticoagulada con warfarina. Tendencias 2006; 73-7.
(14) Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P450 2C9 in a caucasian and a black african population. Br J Cli Pharmacol 2001; 52(4): 447-50.
(15) Schalekamp T, Brassé BP, Roijers JF, Chahid Y, van Geest-Daalderop JH, de Vries-Goldschmeding H, et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 2006; 80(1): 13-22.
(16) Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Fye-Anderson A, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358: 999-1008.
(17) Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clin Pharmacol Ther 2008; 83(2): 312-21.
(18) Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2008. (Epub ahead of print).
(19) Meckley LM, Wittkowsky AK, Rieder MJ, Rettie AE, Veenstra DL. An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients. Thromb Haemost 2008; 100(2): 229-39.
(20) Haug KB, Sharikabad MN, Kringen MK, Narum S, Sjaatil ST, Johansen PW, et al. Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction. Thromb J 2008; 6: 7.
(21) Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics 1997; 7: 203-10.
(22) Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 1996; 333: 447-58.
(23) Aithal GP, Day CP, Kesteven P, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1998; 353: 717-9.
(24) Wang D, Chen H, Momary KM, Cavallari LH, Johnson JA, Sadee W. Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood 2008; 112 (4): 1013-21.
(25) Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005; 14(13): 1745-51.
(26) Casais P, Sánchez Luceros A, Meschengieser S, Fondevila C, Santarelli M, Lazzari M. Bleeding risk factors in chronic oral anticoagulation with acenocumarol. Am J Hematol 2000; 63: 192-6.
(27) Lindh JD, Lundgren S, Holm L, Alfredsson L, Rane A. Several-fold increase in risk of overanticoagulation by CYP2C9 mutations. Clin Pharmacol Ther 2005; 78(5): 540-50.
(28) Voora D, Eby C, Linder MW, Milligan PE, Bukaveckas BL, McLeod HL, et al. Prospective dosing of warfarin based on cytochrome P-450 2 C9 genotype. Thromb Haemost 2005; 93(4): 700-5.
(29) Hillman M, Wilke RA, Yale SH, Vidaillet HJ, Caldwell MD, Glurich I, et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res 2005; 3(3): 137-45.
(30) Sconce EA, Khan T, Wynne H, Avery P, Monkhouse L, King B, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329-33.
(31) Gage BF, Lesko LJ. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 2008; 25(1): 45-51.
(32) Washington University Medical Center. Barnes-Jewish Hospital. Warfarin dosing. 2008. Obtenido de: www.warfarindosing.org (Consulta: 20 octubre 2008).
(33) Perini J, Struchiner C, Silva-Assunção E, Santana I, Rangel F, Ojopi E, et al. Pharmacogenetics of warfarin: development of a dosing algorithm for Brazilian patients. Clin Pharmacol Ther 2008; 84: 722-8.
(34) Wen MS, Lee M, Chen JJ, Chuang HP, Lu LS, Chen CH, et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Ther 2008; 84(1): 83-9.
(35) Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J 2006; 7: 99-111.
(36) Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111(8): 4106-12.
(37) Cooper GM, Johnson JA, Langaee TY, Feng H, Stanaway IB, Schwarz UI, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 2008; 112(4): 1022-7.
(38) Lesko LJ. The critical path of warfarin dosing: finding an optimal dosing strategy using pharmacogenetics. Clin Pharmacol Ther 2008; 84(3): 301-3.
(39) U.S. Food and Drug Administration. FDA Approves updated warfarin (coumadin) prescribing information. FDA News 2007. Obtenido de: www.fda.gov/bbs/topics/news/2007/new01684.html (Consulta: 20 octubre 2008).
(40) Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165: 1095-106.
(2) Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119: 8S-21S.
(3) Weinshilboum R. Inheritance and drug response. N Engl J Med 2003; 348: 529-37.
(4) Evans WE, Relling M. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286: 487-91.
(5) Rettie AE, Tai G. The pharmocogenomics of warfarin: closing in on personalized medicine. Mol Interv 2006; 6: 223-7.
(6) Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: A HuGEnet™ systematic review and meta-analysis. Genet Med 2005; 7(2): 97-104.
(7) Raggio V, Neira P, Esperón P, Lorenzo M, Stoll M. Respuesta terapéutica inadecuada a la warfarina en un paciente genéticamente susceptible. Rev Med Urug 2005; 21: 242-6.
(8) Raggio V, Esperón P, Lorenzo M, Taub I, Cuesta A, Rodríguez A, et al. Variantes de los genes CYP2C9 y apolipoproteína E en la respuesta individual a la warfarina. Rev Urug Cardiol 2006; 21: 104-16.
(9) Rieder MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352(22): 2285-93.
(10) D’Andrea G, D’Ambrosio RL, Di Perna P, Chetta M, Santacroce R, Brancaccio V, et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 2005; 105(2): 645-9.
(11) XXI Congreso Uruguayo de Cardiología: temas libres. Rev Urug Cardiol 2005; 20(3): 199. Obtenido de: http://www.scielo.edu.uy/scielo.php?script=sci_arttext&pid=S0797-00482005000300007&lng=es&nrm=iso&tlng=es (Consulta: 20 octubre 2008).
(12) Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1. Rationale and perspectives. Thrombosis Research 2007; 120: 1-10.
(13) Estrada N, Sevrini I, Prego A, Giusti M, Azambuja C, Álvarez Rocha A. Prevalencia de los polimorfismos del CYP2C9 en una población uruguaya anticoagulada con warfarina. Tendencias 2006; 73-7.
(14) Scordo MG, Aklillu E, Yasar U, Dahl ML, Spina E, Ingelman-Sundberg M. Genetic polymorphism of cytochrome P450 2C9 in a caucasian and a black african population. Br J Cli Pharmacol 2001; 52(4): 447-50.
(15) Schalekamp T, Brassé BP, Roijers JF, Chahid Y, van Geest-Daalderop JH, de Vries-Goldschmeding H, et al. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther 2006; 80(1): 13-22.
(16) Schwarz UI, Ritchie MD, Bradford Y, Li C, Dudek SM, Fye-Anderson A, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358: 999-1008.
(17) Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, et al. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin. Clin Pharmacol Ther 2008; 83(2): 312-21.
(18) Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MJ, Bumpstead S, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2008. (Epub ahead of print).
(19) Meckley LM, Wittkowsky AK, Rieder MJ, Rettie AE, Veenstra DL. An analysis of the relative effects of VKORC1 and CYP2C9 variants on anticoagulation related outcomes in warfarin-treated patients. Thromb Haemost 2008; 100(2): 229-39.
(20) Haug KB, Sharikabad MN, Kringen MK, Narum S, Sjaatil ST, Johansen PW, et al. Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction. Thromb J 2008; 6: 7.
(21) Crespi CL, Miller VP. The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH: cytochrome P450 oxidoreductase. Pharmacogenetics 1997; 7: 203-10.
(22) Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys 1996; 333: 447-58.
(23) Aithal GP, Day CP, Kesteven P, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1998; 353: 717-9.
(24) Wang D, Chen H, Momary KM, Cavallari LH, Johnson JA, Sadee W. Regulatory polymorphism in vitamin K epoxide reductase complex subunit 1 (VKORC1) affects gene expression and warfarin dose requirement. Blood 2008; 112 (4): 1013-21.
(25) Yuan HY, Chen JJ, Lee MT, Wung JC, Chen YF, Charng MJ, et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005; 14(13): 1745-51.
(26) Casais P, Sánchez Luceros A, Meschengieser S, Fondevila C, Santarelli M, Lazzari M. Bleeding risk factors in chronic oral anticoagulation with acenocumarol. Am J Hematol 2000; 63: 192-6.
(27) Lindh JD, Lundgren S, Holm L, Alfredsson L, Rane A. Several-fold increase in risk of overanticoagulation by CYP2C9 mutations. Clin Pharmacol Ther 2005; 78(5): 540-50.
(28) Voora D, Eby C, Linder MW, Milligan PE, Bukaveckas BL, McLeod HL, et al. Prospective dosing of warfarin based on cytochrome P-450 2 C9 genotype. Thromb Haemost 2005; 93(4): 700-5.
(29) Hillman M, Wilke RA, Yale SH, Vidaillet HJ, Caldwell MD, Glurich I, et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res 2005; 3(3): 137-45.
(30) Sconce EA, Khan T, Wynne H, Avery P, Monkhouse L, King B, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329-33.
(31) Gage BF, Lesko LJ. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 2008; 25(1): 45-51.
(32) Washington University Medical Center. Barnes-Jewish Hospital. Warfarin dosing. 2008. Obtenido de: www.warfarindosing.org (Consulta: 20 octubre 2008).
(33) Perini J, Struchiner C, Silva-Assunção E, Santana I, Rangel F, Ojopi E, et al. Pharmacogenetics of warfarin: development of a dosing algorithm for Brazilian patients. Clin Pharmacol Ther 2008; 84: 722-8.
(34) Wen MS, Lee M, Chen JJ, Chuang HP, Lu LS, Chen CH, et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Ther 2008; 84(1): 83-9.
(35) Wadelius M, Pirmohamed M. Pharmacogenetics of warfarin: current status and future challenges. Pharmacogenomics J 2006; 7: 99-111.
(36) Caldwell MD, Awad T, Johnson JA, Gage BF, Falkowski M, Gardina P, et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111(8): 4106-12.
(37) Cooper GM, Johnson JA, Langaee TY, Feng H, Stanaway IB, Schwarz UI, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 2008; 112(4): 1022-7.
(38) Lesko LJ. The critical path of warfarin dosing: finding an optimal dosing strategy using pharmacogenetics. Clin Pharmacol Ther 2008; 84(3): 301-3.
(39) U.S. Food and Drug Administration. FDA Approves updated warfarin (coumadin) prescribing information. FDA News 2007. Obtenido de: www.fda.gov/bbs/topics/news/2007/new01684.html (Consulta: 20 octubre 2008).
(40) Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165: 1095-106.
Publicado
2008-12-31
Cómo citar
1.
Esperón P, Raggio V, Goyeneche L, Lorenzo M, Taub I, Stoll M. Genotipo de los genes VKORC1 y CYP2C9 en la respuesta individual a la warfarina. Rev. Méd. Urug. [Internet]. 31 de diciembre de 2008 [citado 18 de diciembre de 2024];24(4):266-7. Disponible en: https://www2.rmu.org.uy/ojsrmu311/index.php/rmu/article/view/520
Sección
Artículos originales
