Revista de Biología Tropical ISSN Impreso: 0034-7744 ISSN electrónico: 2215-2075

Relevance of the ancestry for the variability of the Drug-Metabolizing Enzymes CYP2C9, CYP2C19 and CYP2D6 polymorphisms in a multiethnic Costa Rican population
PT 64-3 set 2016


Costa Rica
genomic ancestry.
Costa Rica
ancestría genética.

How to Cite

Céspedes-Garro, C., Rodrigues-Soares, F., Jiménez-Arce, G., G. Naranjo, M.-E., Tarazona-Santos, E., Fariñas, H., Barrantes, R., & Llerena, A. (2016). Relevance of the ancestry for the variability of the Drug-Metabolizing Enzymes CYP2C9, CYP2C19 and CYP2D6 polymorphisms in a multiethnic Costa Rican population. Revista De Biología Tropical, 64(3).


CYP2C9, CYP2C19 and CYP2D6 metabolize around 40% of drugs and their genes vary across populations. The Costa Rican population has a trihybrid ancestry and its key geographic location turns it into a suitable scenario to evaluate interethnic differences across populations. This study aims to describe the diversity of CYP2C9, CYP2C19 and CYP2D6 polymorphisms in Costa Rican populations in the context of their ancestry. A total of 448 healthy individuals were included in the study: Bribri (n= 47), Cabécar (n= 27), Maleku (n= 16), Guaymí (n= 30), Huetar (n= 48), Chorotega (n= 41), Admixed/Mestizos from the Central Valley/Guanacaste (n= 189), and Afro-Caribbeans (n= 50) from Limón. CYP2C9 (alleles *2, *3, *6) and CYP2C19 (*2, *3, *4, *5, *17) genotypes were determined by Real-Time PCR. African, European and Native American ancestry were inferred using 87 ancestry informative markers. The frequency of the decreased activity allele CYP2C9*2 is lower in the self-reported Amerindian groups compared to the admixed population, and the highest frequencies of CYP2C19*2 (null activity) and the CYP2C19*17 (increased activity) were found in the self-reported Afro-Caribbean population. Moreover, a frequency of 0.7 % CYP2C9 gPMs in the Admixed population and a variable frequency of CYP2C19 gUMs (0.0-32.6 %, more prevalent in Afro-Caribbeans) in Costa Rican populations, was found. Finally, the following alleles were positively correlated with genomic African ancestry and negatively correlated with genomic Native American ancestry: CYP2D6*5 (null activity), CYP2D6*17 (decreased activity), CYP2D6*29 (decreased activity) and CYP2C19*17 (increased activity). No correlation for CYP2C9 polymorphisms and genomic ancestry was found. Further studies assessing the CYP2C9 and CYP2C19 sequence in these populations, preferentially by sequencing these genes, are warranted.


Alexander, D. H., Novembre, J., & Lange, K. (2009). Fast model-based estimation of ancestry in unrelated individuals. Genome Research, 19(9), 1655-1664.

Altar, C. A., Carhart, J. M., Allen, J. D., Hall-Flavin, D. K., Dechairo, B. M., & Winner, J. G. (2015). Clinical validity: Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes. The Pharmacogenomics Journal, 15(5), 443-451.

Azofeifa, J., Hahn, M., Ruiz, E., Hummerich, L., Morales, A. I., Jiménez, G., & Barrantes, R. (2004). The STR polymorphism (AAAAT)n within the intron 1 of the tumor protein 53 (TP53) locus in 17 populations of different ethnic groups of Africa, America, Asia and Europe. Revista de Biologia Tropical, 52(3), 645-657.

Azofeifa, J., Ruiz, E., & Barrantes, R. (2001). Blood group, red cell, and serum protein variation in the Cabécar and Huetar, two Chibchan Amerindian tribes of Costa Rica. American Journal of Human Biology: The Official Journal of the Human Biology Council, 13(1), 57-64.

Barrantes, R. (1993). Diversidad genética y mezcla racial en los amerindios de Costa Rica y Panamá. Revista de Biologia Tropical, 41(3 A), 379-384.

Barrantes, R., Smouse, P. E., Mohrenweiser, H. W., Gershowitz, H., Azofeifa, J., Arias, T. D., & Neel, J. V. (1990). Microevolution in lower Central America: genetic characterization of the Chibcha-speaking groups of Costa Rica and Panama, and a consensus taxonomy based on genetic and linguistic affinity. American Journal of Human Genetics, 46(1), 63-84.

Barrantes, R., Smouse, P. E., Neel, J. V., Mohrenweiser, H. W., & Gershowitz, H. (1982). Migration and genetic infrastructure of the central American Guaymí and their affinities with other tribal groups. American Journal of Physical Anthropology, 58(2), 201-214.

Bieber, H., Bieber, S. W., Rodewald, A., & Barrantes, R. (1996). Microevolution and genetic affinities among six Amerindian tribes of lower Central America: comparative genetic study of serum proteins. Human Biology, 68(6), 929-953.

Center for Drug Evaluation and Research. (2015). Genomics - Table of Pharmacogenomic Biomarkers in Drug Labeling. Retrieved from

Céspedes-Garro, C., Fricke-Galindo, I., Naranjo, M. E. G., Rodrigues-Soares, F., Fariñas, H., de Andrés, F., López-López, M., Peñas-Lledó, E. M., & Llerena, A. (2015). Worldwide interethnic variability and geographical distribution of CYP2C9 genotypes and phenotypes. Expert Opinion on Drug Metabolism & Toxicology, 11(12), 1-13.

Céspedes-Garro, C., Jiménez-Arce, G., Naranjo, M. E. G., Barrantes, R., & Llerena, A. (2014a). Ethnic background and CYP2D6 genetic polymorphisms in Costa Ricans. Revista de Biología Tropical, 62(4), 1659-1671.

Céspedes-Garro, C., Naranjo, M. E. G., Ramírez, R., Serrano, V., Fariñas, H., Barrantes, R., & Llerena, A. (2014b). Pharmacogenetics in Central American healthy volunteers: interethnic variability. Drug Metabolism and Personalized Therapy, 30(1), 19-31.

CYP2C19 allele nomenclature. (2015). Retrieved from

CYP2C9 allele nomenclature. (2015). Retrieved from

CYP2D6 allele nomenclature. (2015). Retrieved June from

Dorado, P., Beltrán, L. J., Machín, E., Peñas-Lledó, E. M., Terán, E., & Llerena, A. (2012a). Losartan hydroxylation phenotype in an Ecuadorian population: influence of CYP2C9 genetic polymorphism, habits and gender. Pharmacogenomics, 13(15), 1711-1717.

Dorado, P., Gallego, A., Peñas-Lledó, E., Terán, E., & Llerena, A. (2014). Relationship between the CYP2C9 IVS8-109A>T polymorphism and high losartan hydroxylation in healthy Ecuadorian volunteers. Pharmacogenomics, 15(11), 1417-1421.

Dorado, P., Machín, E., De Andrés, F., Naranjo, M. E. G., Peñas-Lledó, E. M., & Llerena, A. (2012b). Development of a HPLC method for the determination of losartan urinary metabolic ratio to be used for the determination of CYP2C9 hydroxylation phenotypes. Drug Metabolism and Drug Interactions, 27(4), 217-223.

Gaedigk, A., Simon, S. D., Pearce, R. E., Bradford, L. D., Kennedy, M. J., & Leeder, J. S. (2008). The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clinical Pharmacology and Therapeutics, 83(2), 234-242.

Ingelman-Sundberg, M., Sim, S. C., Gómez, A., & Rodríguez-Antona, C. (2007). Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacology & Therapeutics, 116(3), 496-526.

Janha, R. E., Worwui, A., Linton, K. J., Shaheen, S. O., Sisay-Joof, F., & Walton, R. T. (2014). Inactive alleles of cytochrome P450 2C19 may be positively selected in human evolution. BMC Evolutionary Biology, 14, 71.

Llerena, A., Álvarez, M., Dorado, P., González, I., Peñas-Lledó, E., Pérez, B., Cobaleda, J., & Calzadilla, L. R. (2014a). Interethnic differences in the relevance of CYP2C9 genotype and environmental factors for diclofenac metabolism in Hispanics from Cuba and Spain. The Pharmacogenomics Journal, 14(3), 229-234.

Llerena, A., Dorado, P., Ramírez, R., González, I., Álvarez, M., Peñas-Lledó, E. M., Pérez, B., & Calzadilla, L. R. (2012). CYP2D6 genotype and debrisoquine hydroxylation phenotype in Cubans and Nicaraguans. The Pharmacogenomics Journal, 12(2), 176-183.

Llerena, A., Naranjo, M. E. G., Rodrigues-Soares, F., Penas-Lledó, E. M., Fariñas, H., & Tarazona-Santos, E. (2014b). Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert Opinion on Drug Metabolism & Toxicology, 10(11), 1569-1583.

Madrigal, L. (2006). Human biology of Afro-Caribbean populations. Cambridge studies in biological and evolutionary anthropology. New York, USA: Cambridge University Press.

Niu, X., Mao, L., Huang, Y., Baral, S., Li, J. Y., Gao, Y., Xia, Y. P., He, Q. W., Wang, M. D., Li, M., Zou, L., Miao, X. P., & Hu, B. (2015). CYP2C19 polymorphism and clinical outcomes among patients of different races treated with clopidogrel: A systematic review and meta-analysis. Journal of Huazhong University of Science and Technology. Medical Sciences = Hua Zhong Ke Ji Da Xue Xue Bao. Yi Xue Ying De Wen Ban = Huazhong Keji Daxue Xuebao. Yixue Yingdewen Ban, 35(2), 147-156.

Peñas-Lledó, E., Guillaume, S., Naranjo, M. E. G., Delgado, A., Jaussent, I., Blasco-Fontecilla, H., Courtet, P., & Llerena, A. (2014). A combined high CYP2D6-CYP2C19 metabolic capacity is associated with the severity of suicide attempt as measured by objective circumstances. The Pharmacogenomics Journal, 15(2), 172-176.

Pereira, L., Zamudio, R., Soares-Souza, G., Herrera, P., Cabrera, L., Hooper, C. C., Cok, J., Combe, J. M., Vargas, G., Prado, W. A., Schneider, S., Kehdy, F., Rodrigues, M. R., Chanock, S. J., Berg, D. E., Gilman, R. H., & Tarazona-Santos, E. (2012). Socioeconomic and nutritional factors account for the association of gastric cancer with Amerindian ancestry in a Latin American admixed population. PloS One, 7(8), e41200.

R Foundation. (2015). R: The R Project for Statistical Computing. Retrieved from

Rolla, R., Gramaglia, C., Dalò, V., Ressico, F., Prosperini, P., Vidali, M., Meola, S., Pollarolo, P., Bellomo, G., Torre, E., & Zeppegno, P. (2014). An observational study of Venlafaxine and CYP2D6 in clinical practice. Clinical Laboratory, 60(2), 225-231.

Ruiz-Narváez, E. A., Santos, F. R., Carvalho-Silva, D. R., Azofeifa, J., Barrantes, R., & Pena, S. D. J. (2005). Genetic variation of the Y chromosome in Chibcha-speaking Amerindians of Costa Rica and Panama. Human Biology, 77(1), 71-91.

Salazar-Flores, J., Torres-Reyes, L. A., Martínez-Cortés, G., Rubi-Castellanos, R., Sosa-Macías, M., Muñoz-Valle, J. F., González-González, C., Ramírez, A., Román, R., Méndez, J. L., Barrera, A., Torres, A., Medina, R., & Rangel-Villalobos, H. (2012). Distribution of CYP2D6 and CYP2C19 polymorphisms associated with poor metabolizer phenotype in five Amerindian groups and western Mestizos from Mexico. Genetic Testing and Molecular Biomarkers, 16(9), 1098-1104.

Santos, M., Ward, R. H., & Barrantes, R. (1994). mtDNA variation in the Chibcha Amerindian Huetar from Costa Rica. Human Biology, 66(6), 963-977.

Santos, P. C. J. L., Soares, R. A. G., Santos, D. B. G., Nascimento, R. M., Coelho, G. L. L. M., Nicolau, J. C., Mill, J. G., Krieger, J. E., & Pereira, A. C. (2011). CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population. BMC Medical Genetics, 12, 13.

Segura-Wang, M., Raventós, H., Escamilla, M., & Barrantes, R. (2010). Assessment of genetic ancestry and population substructure in Costa Rica by analysis of individuals with a familial history of mental disorder. Annals of Human Genetics, 74(6), 516-524.

Seripa, D., Latina, P., Fontana, A., Gravina, C., Lattanzi, M., Savino, M., Gallo, A. P., Melchionda, G., Santini, S. A., Margaglione, M., Copetti, M., di Mauro, L., Panza, F., Greco, A., & Pilotto, A. (2015). Role of CYP2D6 polymorphisms in the outcome of postoperative pain treatment. Pain Medicine, 16(10), 2012-2023.

Sistonen, J., Fuselli, S., Palo, J. U., Chauhan, N., Padh, H., & Sajantila, A. (2009). Pharmacogenetic variation at CYP2C9, CYP2C19, and CYP2D6 at global and microgeographic scales. Pharmacogenetics and Genomics, 19(2), 170-179.

Sosa-Macias, M., Moya, G. E., Llerena, A., Ramírez, R., Terán, E., Peñas-Lledó, E. M., Tarazona-Santos, E., Galaviz-Hernández, C., Céspedes-Garro, C., & Acosta, H. (2015). Population pharmacogenetics of Ibero-Latinoamerican populations (MESTIFAR 2014). Pharmacogenomics, 16(7), 673-676.

Tabata, N., Hokimoto, S., Akasaka, T., Arima, Y., Sakamoto, K., Yamamoto, E., Tsujita, K., Izumiya, Y.,Yamamuro, M., Kojima, S., Kaikita, K., Kumagae, N., Morita, K., Oniki, K., Nakagawa, K., Matsui, K., & Ogawa, H. (2015). Patients with both CYP2C19 loss-of-function allele and peripheral endothelial dysfunction are significantly correlated with adverse cardiovascular events following coronary stent implantation. Journal of Cardiology, 67(1), 104-109.

The International HapMap Consortium. (2010). Integrating common and rare genetic variation in diverse human populations. Nature, 467(7311), 52-58.

Vargens, D. D., Petzl-Erler, M. L., & Suarez-Kurtz, G. (2012). Distribution of CYP2C polymorphisms in an Amerindian population of Brazil. Basic & Clinical Pharmacology & Toxicology, 110(4), 396-400.

Vicente, J., González-Andrade, F., Soriano, A., Fanlo, A., Martínez-Jarreta, B., & Sinués, B. (2014). Genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 in Ecuadorian Mestizo and Spaniard populations: a comparative study. Molecular Biology Reports, 41(3), 1267-1272.

Yaeger, R., Avila-Bront, A., Abdul, K., Nolan, P. C., Grann, V. R., Birchette, M. G., Choudhry, S., Burchard, E. G., Beckman, K. B., Gorroochurn, P., Ziv, E., Consedine, N. S., & Joe, A. K. (2008). Comparing genetic ancestry and self-described race in african americans born in the United States and in Africa. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology, 17(6), 1329-1338.

Yang, J., Chen, Y., Li, X., Wei, X., Chen, X., Zhang, L., Zhang, Y., Xu, Q., Wang, H., Li, Y., Lu, C., Chen, W., Zeng, C., & Yin, T. (2013). Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. International Journal of Cardiology, 168(4), 4234-4243.

Youngster, I., Zachor, D. A., Gabis, L. V., Bar-Chaim, A., Benveniste-Levkovitz, P., Britzi, M., Soback, S., Ziv-Baran, T., & Berkovitch, M. (2014). CYP2D6 genotyping in paediatric patients with autism treated with risperidone: a preliminary cohort study. Developmental Medicine and Child Neurology, 56(10), 990-994.



Download data is not yet available.