CYP2C9 and VKORC1-1639 genetic polymorphisms involved in warfarin pharmacogenetics and pharmacodynamics in Latin American population

Authors

DOI:

https://doi.org/10.5377/torreon.v10i27.10842

Keywords:

warfarin, CYP2C9, VKORC1-1639, polymorphism

Abstract

Warfarin is the most common anticoagulant used worldwide for prevention and treatment of thromboembolic events. Polymorphisms in the CYP2C9 and VKORC1 -1639 genes have been associated with variability in the response to warfarin in several populations. The aim of this research is to determine the frequency of these polymorphisms in Latin American population. The identification of the presence of polymorphisms can guarantee the safest and most effective use of warfarin by predicting the appropriate dose for each patient.

We included eleven studies with frequency data of genetic polymorphisms in 2,830 Latin American patients. The allelic variants CYP2C9 *1 / *2 and CYP2C9 *1 / *3 were more frequent in the study population, with 13.15% and 6.93% respectively. The allelic variant *3 / *3 was present in 0.17%. As for the polymorphisms of the VKORC1 -1639 gene frequencies of 49.11%, 33% and 17% were reported for the GA, GG and AA variants respectively.

Frequency of the allelic variants in the genes CYPC9 and VKORC1, in the Latin American population, allows to establish starting points to suggest the genotypes that should be evaluated before the indication of the warfarin dose. Comparing the frequency of polymorphisms in the CYP2C9 and VKORC1 -1639 genes in the Latin American population with other populations, similarities are observed with the populations of origin.

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References

Al-Eitan, L. N., Almasri, A. Y., & Khasawneh, R. H. (2018). Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy. Genes, 9(12), 578. https://doi.org/10.3390/genes9120578

Arribas IA. (2010). Farmacogenética y variabilidad interindividual en la respuesta a los medicamentos. Academia de Farmacia “Reino de Aragón. http://www.academiadefarmaciadearagon.es/docs/documentos/documento21.pdf

Benavides, F., Grossman, N., Poggi, H., Nieto, E., Bertrán, A., Araos, D., Vásquez, M., Ibarra, I., Cáceres, F., Espinoza, K., Lagos, M., & Repetto M, G. (2015). Efecto de las variantes de VKORC1 y CYP2C9 sobre la dosis de anticoagulantes orales en individuos chilenos Revista medica de Chile, 143(11), 1369–1376. https://doi.org/10.4067/S0034-98872015001100001

Botton, M. R., Bandinelli, E., Rohde, L. E., Amon, L. C., & Hutz, M. H. (2011). Influence of genetic, biological and pharmacological factors on warfarin dose in a Southern Brazilian population of European ancestry. British journal of clinical pharmacology, 72(3), 442–450. https://doi.org/10.1111/j.1365-2125.2011.03942.x

Bryk, A. H., Wypasek, E., Plens, K., Awsiuk, M., & Undas, A. (2018). Bleeding predictors in patients following venous thromboembolism treated with vitamin K antagonists: Association with increased number of single nucleotide polymorphisms. Vascular pharmacology, 106, 22–27. https://doi.org/10.1016/j.vph.2018.02.002

Cabrero J. y Camacho P. Fundamentos de Genética de Poblaciones. http://sesbe.org/sites/sesbe.org/files/recursos-sesbe/fundamentos_GdeP.pdf

Castelán-Martínez, O. D., Hoyo-Vadillo, C., Sandoval-García, E., Sandoval-Ramírez, L., González-Ibarra, M., Solano-Solano, G., Gómez-Díaz, R. A., Parra, E. J., Cruz, M., & Valladares-Salgado, A. (2013). Allele frequency distribution of CYP2C9 2 and CYP2C9 3 polymorphisms in six Mexican populations. Gene, 523(2), 167–172. https://doi.org/10.1016/j.gene.2013.03.128

Cavallari, L. H., Shin, J., & Perera, M. A. (2011). Role of pharmacogenomics in the management of traditional and novel oral anticoagulants. Pharmacotherapy, 31(12), 1192–1207. https://doi.org/10.1592/phco.31.12.1192

Céspedes-Garro, C., Naranjo, M. G., Rodrigues-Soares, F., LLerena, A., Duconge, J., Montané-Jaime, L. K., Roblejo, H., Fariñas, H., Campos, M. L., Ramírez, R., Serrano, V., Villagrán, C. I., & Peñas-LLedó, E. M. (2016). Pharmacogenetic research activity in Central America and the Caribbean: a systematic review. Pharmacogenomics, 17(15), 1707–1724. https://doi.org/10.2217/pgs-2016-0053

Cifuentes, R., Murillo, J. y Avella, E. (2016). Predicción a la sensibilidad a la warfarina con base en polimorfismos de los genes VKORC1 y CYP2C9 en pacientes colombianos. Biomédica, 36, 91-100. https://www.revistabiomedica.org/index.php/biomedica/article/view/2795

Claudio-Campos, K., Orengo-Mercado, C., Renta, J. Y., Peguero, M., García, R., Hernández, G., Corey, S., Cadilla, C. L., & Duconge, J. (2015). Pharmacogenetics of healthy volunteers in Puerto Rico. Drug metabolism and personalized therapy, 30(4), 239–249. https://doi.org/10.1515/dmpt-2015-0021

Cullell, N., Carrera, C., Muiño, E., Torres, N., Krupinski, J., & Fernandez-Cadenas, I. (2018). Pharmacogenetic studies with oral anticoagulants. Genome-wide association studies in vitamin K antagonist and direct oral anticoagulants. Oncotarget, 9(49), 29238–29258. https://doi.org/10.18632/oncotarget.25579

Daneshjou, R., Tatonetti, N. P., Karczewski, K. J., Sagreiya, H., Bourgeois, S., Drozda, K., Burmester, J. K., Tsunoda, T., Nakamura, Y., Kubo, M., Tector, M., Limdi, N. A., Cavallari, L. H., Perera, M., Johnson, J. A., Klein, T. E., & Altman, R. B. (2013). Pathway analysis of genome-wide data improves warfarin dose prediction. BMC genomics, 14 Suppl 3(Suppl 3), S11. https://doi.org/10.1186/1471-2164-14-S3-S11

Dean, L. (2012). Warfarin Therapy and VKORC1 and CYP Genotype. In V. M. Pratt (Eds.) et. al., Medical Genetics Summaries. National Center for Biotechnology Information (US).

Dilge Taşkın, B., Kula, S., Ergün, M. A., Altun, D., Olguntürk, R., Tunaoğlu, F. S., Oğuz, A. D., & Gürsel, T. (2016). The effect of CYP2C9 and VKORC1 genetic polymorphisms on warfarin dose requirements in a pediatric population. Anatolian journal of cardiology, 16(10), 791–796. https://doi.org/10.14744/AnatolJCardiol.2015.6150

Dong, A. N., Tan, B. H., Pan, Y., & Ong, C. E. (2018). Cytochrome P450 genotype-guided drug therapies: An update on current states. Clinical and experimental pharmacology & physiology, 45(10), 991–1001. https://doi.org/10.1111/1440-1681.12978

Duconge, J., Cadilla, C. L., Windemuth, A., Kocherla, M., Gorowski, K., Seip, R. L., Bogaard, K., Renta, J. Y., Piovanetti, P., D'Agostino, D., Santiago-Borrero, P. J., & Ruaño, G. (2009). Prevalence of combinatorial CYP2C9 and VKORC1 genotypes in Puerto Ricans: implications for warfarin management in Hispanics. Ethnicity & disease, 19(4), 390–395. https://www.ncbi.nlm.nih.gov/pubmed/20073138

Flockhart, D. A., O'Kane, D., Williams, M. S., Watson, M. S., Flockhart, D. A., Gage, B., Gandolfi, R., King, R., Lyon, E., Nussbaum, R., O'Kane, D., Schulman, K., Veenstra, D., Williams, M. S., Watson, M. S., & ACMG Working Group on Pharmacogenetic Testing of CYP2C9, VKORC1 Alleles for Warfarin Use (2008). Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genetics in medicine : official journal of the American College of Medical Genetics, 10(2), 139–150. https://doi.org/10.1097/GIM.0b013e318163c35f

Gaikward, T., Ghosh K, Kulkarni B, Kulkarni V, Ross C. and Shetty S. (2013). Influence of CYP2C9 and VKORC1 gene polymorphism on warfarin dosage, over anticoagulation and other adverse outcomes in Indian Population. European Journal of Pharmacology, 710:80-84. https://www.sciencedirect.com/science/article/abs/pii/S0014299913002951

Galvez, J. M., Restrepo, C. M., Contreras, N. C., Alvarado, C., Calderón-Ospina, C. A., Peña, N., Cifuentes, R. A., Duarte, D., Laissue, P., & Fonseca, D. J. (2018). Creating and validating a warfarin pharmacogenetic dosing algorithm for Colombian patients. Pharmacogenomics and personalized medicine, 11, 169–178. https://doi.org/10.2147/PGPM.S170515

Golwala, H., Jackson, L. R., 2nd, Simon, D. N., Piccini, J. P., Gersh, B., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Fonarow, G. C., Peterson, E. D., Thomas, K. L., & Outcomes Registry for Better Informed Treatment for Atrial Fibrillation (ORBIT-AF) Registry (2016). Racial/ethnic differences in atrial fibrillation symptoms, treatment patterns, and outcomes: Insights from Outcomes Registry for Better Informed Treatment for Atrial Fibrillation Registry. American heart journal, 174, 29–36. https://doi.org/10.1016/j.ahj.2015.10.028

Guerrero, F. (2009). Farmacogenética de Warfarina. Revista Médica Sanitas, 12(2): 8-12. http://www.gbcbiotech.com/laboratorio/assets/farmacogenetica-de-warfarina.pdf

Hosseinkhani, Z., Sadeghalvad, M., Norooznezhad, F., Khodarahmi, R., Fazilati, M., Mahnam, A., Fattahi, A., & Mansouri, K. (2018). The effect of CYP2C9*2, CYP2C9*3, and VKORC1-1639 G>A polymorphism in patients under warfarin therapy in city of Kermanshah. Research in pharmaceutical sciences, 13(4), 377–384. https://doi.org/10.4103/1735-5362.235165

Isaza, C, Henaao, J. y Beltrán, L. (2010). Resistencia y Sensibilidad a Warfarina. Investigaciones ANDINA, 12(20): 100. http://scielo.sld.cu/scielo.php?script=sci_arttext&pid=S1025-02552014000200009

Kaye, J. B., Schultz, L. E., Steiner, H. E., Kittles, R. A., Cavallari, L. H., & Karnes, J. H. (2017). Warfarin Pharmacogenomics in Diverse Populations. Pharmacotherapy, 37(9), 1150–1163. https://doi.org/10.1002/phar.1982

Kliegman, R., Stanton, B., y Gene, J. Farmacogenética, farmacogenómica y el concepto de medicina personalizada. Nelson. Tratado de pediatría. Edición 19. Capítulo 56: 1-12. http://www.studentconsult.es/ficheros/booktemplate/9788480869591/files/056_0_contbb.pdf

Li, J., Wang, L., Hu, J., & Xu, G. (2015). Warfarin use and the risks of stroke and bleeding in hemodialysis patients with atrial fibrillation: A systematic review and a meta-analysis. Nutrition, metabolism, and cardiovascular diseases : NMCD, 25(8), 706–713. https://doi.org/10.1016/j.numecd.2015.03.013

Limdi, N. A., Arnett, D. K., Goldstein, J. A., Beasley, T. M., McGwin, G., Adler, B. K., & Acton, R. T. (2008). Influence of CYP2C9 and VKORC1 on warfarin dose, anticoagulation attainment and maintenance among European-Americans and African-Americans. Pharmacogenomics, 9(5), 511–526. https://doi.org/10.2217/14622416.9.5.511

Limdi, N. A., Wadelius, M., Cavallari, L., Eriksson, N., Crawford, D. C., Lee, M. T., Chen, C. H., Motsinger-Reif, A., Sagreiya, H., Liu, N., Wu, A. H., Gage, B. F., Jorgensen, A., Pirmohamed, M., Shin, J. G., Suarez-Kurtz, G., Kimmel, S. E., Johnson, J. A., Klein, T. E., Wagner, M. J., … International Warfarin Pharmacogenetics Consortium (2010). Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood, 115(18), 3827–3834. https://doi.org/10.1182/blood-2009-12-255992

Liu, N., Irvin, M. R., Zhi, D., Patki, A., Beasley, T. M., Nickerson, D. A., Hill, C. E., Chen, J., Kimmel, S. E., & Limdi, N. A. (2017). Influence of common and rare genetic variation on warfarin dose among African-Americans and European-Americans using the exome array. Pharmacogenomics, 18(11), 1059–1073. https://doi.org/10.2217/pgs-2017-0046

Liu, R., Cao, J., Zhang, Q., Shi, X. M., Pan, X. D., & Dong, R. (2017). Clinical and genetic factors associated with warfarin maintenance dose in northern Chinese patients with mechanical heart valve replacement. Medicine, 96(2), e5658. https://doi.org/10.1097/MD.0000000000005658

Miklosz, J., Kalaska, B., & Mogielnicki, A. (2018). Pharmacogenetic considerations of anticoagulant medication. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 69(4), 10.26402/jpp.2018.4.01. https://doi.org/10.26402/jpp.2018.4.01

Miranda, C., Roco, A., Garay, J., Squicciarini, V., Tamayo, E., Agúndez, J., et.al. (2011). Determinación del polimorfismo de CYP2C9*2 y su relación con la farmacocinética de acenocumarol en voluntarios sanos. Revista Chilena de cardiología, 30, 218-224. https://scielo.conicyt.cl/pdf/rchcardiol/v30n3/art05.pdf

Moyer, T. P., O'Kane, D. J., Baudhuin, L. M., Wiley, C. L., Fortini, A., Fisher, P. K., Dupras, D. M., Chaudhry, R., Thapa, P., Zinsmeister, A. R., & Heit, J. A. (2009). Warfarin sensitivity genotyping: a review of the literature and summary of patient experience. Mayo Clinic proceedings, 84(12), 1079–1094. https://doi.org/10.4065/mcp.2009.0278

Natarajan, S., Ponde, C. K., Rajani, R. M., Jijina, F., Gursahani, R., Dhairyawan, P. P., & Ashavaid, T. F. (2013). Effect of CYP2C9 and VKORC1 genetic variations on warfarin dose requirements in Indian patients. Pharmacological reports : PR, 65(5), 1375–1382. https://doi.org/10.1016/s1734-1140(13)71496-8

Parra, E. J., Botton, M. R., Perini, J. A., Krithika, S., Bourgeois, S., Johnson, T. A., Tsunoda, T., Pirmohamed, M., Wadelius, M., Limdi, N. A., Cavallari, L. H., Burmester, J. K., Rettie, A. E., Klein, T. E., Johnson, J. A., Hutz, M. H., & Suarez-Kurtz, G. (2015). Genome-wide association study of warfarin maintenance dose in a Brazilian sample. Pharmacogenomics, 16(11), 1253–1263. https://doi.org/10.2217/PGS.15.73

Perini, J. A., Vargens, D. D., Santana, I. S., Moriguchi, E. H., Ribeiro-Dos-Santos, A. K., Tsutsumi, M., & Suarez-Kurtz, G. (2009). Pharmacogenetic polymorphisms in Brazilian-born, first-generation Japanese descendants. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 42(12), 1179–1184. https://doi.org/10.1590/s0100-879x2009001200010

Raggio V, Neira P, Esperón P, Lorenzo M and Stoll M. (2005). Respuesta terapéutica inadecuada a la warfarina en pacientes genéticamente susceptibles. Revista médica Uruguay, 21:242-246. http://www.scielo.edu.uy/pdf/rmu/v21n3/v21n3a11.pdf

Razavi, F. E., Zarban, A., Hajipoor, F., & Naseri, M. (2017). The allele frequency of CYP2C9 and VKORC1 in the Southern Khorasan population. Research in pharmaceutical sciences, 12(3), 211–221. https://doi.org/10.4103/1735-5362.207202

Scibona, P., Redal, M. A., Garfi, L. G., Arbelbide, J., Argibay, P. F., & Belloso, W. H. (2012). Prevalence of CYP2C9 and VKORC1 alleles in the Argentine population and implications for prescribing dosages of anticoagulants. Genetics and molecular research : GMR, 11(1), 70–76. https://doi.org/10.4238/2012.January.9.8

Seng, K., Gin, G., Sangkar, V. and Phipps, E. (2003). Frequency of Cytochrome P450 2C9 (CYP2C9) alleles in three ethnic groups in Malaysia. Asia Pacific Journal of Molecular Biology and biotechnology,11(2), 83-91. https://pdfs.semanticscholar.org/265a/677df9c62f76965f7797c375696879fe1bf6.pdf

Shen, A. Y., Yao, J. F., Brar, S. S., Jorgensen, M. B., & Chen, W. (2007). Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. Journal of the American College of Cardiology, 50(4), 309–315. https://doi.org/10.1016/j.jacc.2007.01.098

Tavares, L. C., Marcatto, L. R., Soares, R., Krieger, J. E., Pereira, A. C., & Santos, P. (2018). Association Between ABCB1 Polymorphism and Stable Warfarin Dose Requirements in Brazilian Patients. Frontiers in pharmacology, 9, 542. https://doi.org/10.3389/fphar.2018.00542

Tsai, C., Marcus, L. Q., Patel, P., & Battistella, M. (2017). Warfarin Use in Hemodialysis Patients With Atrial Fibrillation: A Systematic Review of Stroke and Bleeding Outcomes. Canadian journal of kidney health and disease, 4, 2054358117735532. https://doi.org/10.1177/2054358117735532

Valentin, I. I., Vazquez, J., Rivera-Miranda, G., Seip, R. L., Velez, M., Kocherla, M., Bogaard, K., Cruz-Gonzalez, I., Cadilla, C. L., Renta, J. Y., Feliu, J. F., Ramos, A. S., Alejandro-Cowan, Y., Gorowski, K., Ruaño, G., & Duconge, J. (2012). Prediction of warfarin dose reductions in Puerto Rican patients, based on combinatorial CYP2C9 and VKORC1 genotypes. The Annals of pharmacotherapy, 46(2), 208–218. https://doi.org/10.1345/aph.1Q190

Valentín, I. I., Rivera, G., Nieves-Plaza, M., Cruz, I., Renta, J. Y., Cadilla, C. L., Feliu, J. F., Seip, R. L., Ruaño, G., & Duconge, J. (2014). Pharmacogenetic association study of warfarin safety endpoints in Puerto Ricans. Puerto Rico health sciences journal, 33(3), 97–104. https://pubmed.ncbi.nlm.nih.gov/25244877/

Villagra, D., Duconge, J., Windemuth, A., Cadilla, C. L., Kocherla, M., Gorowski, K., Bogaard, K., Renta, J. Y., Cruz, I. A., Mirabal, S., Seip, R. L., & Ruaño, G. (2010). CYP2C9 and VKORC1 genotypes in Puerto Ricans: A case for admixture-matching in clinical pharmacogenetic studies. Clinica chimica acta; international journal of clinical chemistry, 411(17-18), 1306–1311. https://doi.org/10.1016/j.cca.2010.05.021

Villegas-Torres, B., Sánchez-Girón, F., Jaramillo-Villafuerte, K., Soberón, X., & Gonzalez-Covarrubias, V. (2015). Genotype frequencies of VKORC1 and CYP2C9 in native and Mestizo populations from Mexico, potential impact for coumarin dosing. Gene, 558(2), 235–240. https://doi.org/10.1016/j.gene.2014.12.068

Wattanachai, N., Kaewmoongkun, S., Pussadhamma, B., Makarawate, P., Wongvipaporn, C., Kiatchoosakun, S., Vannaprasaht, S., & Tassaneeyakul, W. (2017). The impact of non-genetic and genetic factors on a stable warfarin dose in Thai patients. European journal of clinical pharmacology, 73(8), 973–980. https://doi.org/10.1007/s00228-017-2265-8

Yoon, Y. R., Shon, J. H., Kim, M. K., Lim, Y. C., Lee, H. R., Park, J. Y., Cha, I. J., & Shin, J. G. (2001). Frequency of cytochrome P450 2C9 mutant alleles in a Korean population. British journal of clinical pharmacology, 51(3), 277–280. https://doi.org/10.1046/j.1365-2125.2001.00340.x

Zhang, J., Chen, Z., & Chen, C. (2016). Impact of CYP2C9, VKORC1 and CYP4F2 genetic polymorphisms on maintenance warfarin dosage in Han-Chinese patients: A systematic review and meta-analysis. Meta gene, 9, 197–209. https://doi.org/10.1016/j.mgene.2016.07.002

Zhang, H., Ma, K., Liu, W., Yang, F., Liu, J., & Zhou, H. (2016). Impact of CYP2C19 gene polymorphism on warfarin maintenance doses in patients with non-valvular atrial fibrillation. Gene, 591(1), 80–84. https://doi.org/10.1016/j.gene.2016.06.046

Published

2021-02-04

How to Cite

Negaresh, S., Silva Arrechavala, J. R., & Corriols, M. (2021). CYP2C9 and VKORC1-1639 genetic polymorphisms involved in warfarin pharmacogenetics and pharmacodynamics in Latin American population. Torreon Universitario Magazine, 10(27), 76–91. https://doi.org/10.5377/torreon.v10i27.10842

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Health and Social services

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